CA1200490A - Compositions for the inhibition of undesired effects of platinum (ii) compounds - Google Patents

Abstract

ABSTRACT
Dithiocarbamic compounds, administered about 0.5 to about 6 hours after Pt(II) compound, have been found to counter the toxicity of the platinum in multicellular organisms (e.g. mammals). Such compositions suitable for intravenous or intraperitoneal administration have been found to have this salutary effect. For example, neoplastic growths in mammals can be treated with cis-diamine or cis-diammine Pt(II) complexes with greatly lessened risk of nephrotoxicity and damage to the digestive system of the mammal, provided the dithiocarbamic compound is timely (and preferably parenterally) administered. Particularly effective dithiocarbamic compounds are monomeric (e.g., where M? is a pharmaceutically acceptable cation and R1 and R2 are lower aliphatic or cycloaliphatic groups) or, less preferably, dimeric, e.g.

Description

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This application is a division of application Serial No. 383,442-S, filed 7 August, 1981.

Technical Field This invention relates to platinum-binding thiocarbamic compounds which are useful for inhibiting the ability of platinum(II) complexes to bond strongly to certain substrates (such as enzymes, particularly enzymes having mercapto or sulhydryl groups) without eliminating the ability of these complexes to bind to certain other substrates such as cellular desoxyribonucleic acid (DNA). An aspect of this invention relates to compositions which are useful for inhibiting platinum(II) toxicity without eliminating the desired physiological efficacy of the platinum(II) compound.
Still another aspect of this invention relates to compositions which are useful for inhibiting platinum(II) toxicity in a live mammal being treated with a physiologically active platinum(II) compound. Still another aspect of this invention relates to chelating agents which are useful for inhibiting the action of a platinum(II) complex in an organism or system having the capability of rapidly degrading the chelating agent. 5till another aspect of this invention relates to platinum~binding dithiocarbamic compounds which react chemically within the body of a living mammal with an earlier-administered toxic platinum(II) compound so as to inhibit selected biochemical effects of platinum in the mammal.

Prior Art Recent studies have shown that a variety of square planar platinum(II) complexes have bene-Eicial physiological properties, despite a strong tendency to be toxic toward living organisms, particularly organisms having dlgestive systems or kidneys or enzymes capable of complexing with platinum(II).
The physiological or pharmacological utility of platinum(II) complexes stems largely from their ability to inhibit harmful organisms or enzymes and neoplastic cell growth. Accordingly, investigators in this field have been looking for ways of utilizing the platinum(II) against tumors or undesirable organisms (pathogenic bacteria, viruses, and the like) without causing excessive damage to healthy cells or tissue. There is evidence indicating that the mechanism for platinum(II) activity against, for example, neoplastic cells is different rom the mechanism of nephrotoxicity, damage to the digestive system, and other undesirable side effects such as nausea and vomiting. If indeed the mechanism for the useful activity of these compounds is different from the mechanisms of the damaging side effects, opportunities should exist for mitigating the side effects without detracting significantly from the desired physiological effects. Noting that the most serious permanent damage from platinum~II) compounds such as cis-dichlorodiammineplatinum (II) is typically found in the kidneys of mammals, a typical practice of cis-dichlorodiammineplatinum (II) administration makes use of mannitol diuresis, coupled with intravenous prehydration, which has been found, for example, to ameliorate acute toxicity in both dogs and humans. See Cvitkovic et al, CANCER 39:1357 (1977) and Hayes et al, CANCER 39:1372 (1977). In addition, a number of thiol reagents have been examined for their effects upon platinu~ toxicity, including cysteine, peni-cillamine, cysteamine, and N-acetylcysteine. Similar experiments have been conducted with thiourea. The following literature references are believed to be representative of the experimental work with thiols and thiourea:
Slater et al, J. Clim. Hematol Oncol, 7:534 (1977).
Connors, T.A. in Advances in Antimicrobial and_ Antineoplastic Chemotherapy, Volume 2, University Park Press, Baltimore, Maryland, 1972, pages 237~238.
Higby et al, Proc. Am. Assoc. Cancer Res. 16:523A
(Abstract) (1975).
Burchenal, J.H. et al, ~iochimie 60, 961-965 (1978).
Dieke, S.~l. et al, J. Pharmacol. Exp. Ther. 83, 195-202 (19~
Atwood, E.B., J. Pharmacol. Exp. Ther. 78, 79-91 (1943).
Filipski, H., et al, Science 204, 181-183 (1979).
These sulphur-containing compounds were presumably selected because o~ the strong ability of both thiols and thiocarbonyls to bond to platinum(II), even to the point of displacing existing ligands and leaving groups. These platinum-binding sulphur compounds are sometimes referred to as "rescue agents", since the hope of the investigators was that the platinum-binding effect would "rescue" the organlsm from kidney damage and the like. Unfortunately, no beneficial effects have so ~ar been reported in those experiments in which a thiol was administered after the platinum(II). Some benefit was reported when cysteine and penicillamine were given before the platinum(II). However, there is also some evidence indicating that cysteine and penacillamine may have the potential to bind to plasma platinum and hence reduce its chemotherapeutic effect. Decreased efficacy of platinum(II) has also been observed in the case of thiourea when the thiourea was administered prior to the platinum(II). Thiourea has been reported to inhibit thyroid hormone production and thus may have other drawbacks.
The chemistry of platinum and the use of platinum in biological systems are both vast fields. It would be difficult to provide even a representative sampling of patents and literature relating to platinum(II) compounds as antitumor agents~ The same could be said regarding the art of platinum complex formation using sulphur-containing ligands. An excellent series of papers regarding platinum treatment of tumors and resulting side effects appears in Cancer Treatment Reports, Volume 63 (1979), beginning at page 1433. U.S.
Patents of interest regarding platinum treatment of neoplastic cells and viruses include Nos. 4,053,587 (Davidson et al), issued October 11, 1977, and 4,137,248 (Gale et al), issued January 30, 1979. The chemical compound cis-dichlorodiammine-platinum (II) is commercially available from Bristol Laboratories Division of Bristol-Myers Company of Syracuse, New York, ~.S.A. as an antineoplastic agent typically indicated for palliative therapy for metastatic testicular and ovarian tumors.

Summary oE the Invention It has now been found that there is a class of dithiocarbamic monomers and dimers which can inhibit the ability of platinum(lI) compounds to bond irreversibly to useful substrates without eliminating the desirable effects of these compounds. The efficacy of these dithiocarbamic compounds in this regard depends upon their administration as compositions with carriers suitable for non-oral introduction into the body of a mammal being treated with such platinum(II) compounds. For example, it has been found that nephrotoxicity of platinum(II) antitumor agents can be ameliorated without significantly interfering with the chemotherapeutic utility of these agents.
It has also been discovered that under appropriate conditions of administration dithiocarbamic compounds are effective not only in inhibiting the nephrotoxicity of platinum(II) compounds used in cancer chemotherapy, but also in reducing -the severity of nausea and vomiting that frequently accompany the administration of such chemotherapeutic compounds.

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The timing of the administration of the dithiocarbamic compounds used in this invention is of great importance. Administering the compounds prior to, coincidential with, or many hours after platinum(II) is likely to provide very little amelioration of the injurious side effects of the platinum. The preferred timing can be described in several ways, e.g. (1) as a period of time after platinum(II) administration (preferably about 0.5 to about 6 hours afterwards), (2) after a certain minimum and preferably before a certai~ maximum number of plasma half-lives of the platinum(II) (optimally after about 4 but before about 8 plasma half-lives), (3) after the desirable physiological effects of the platinum(II) have been initiated but prior to about 6 hours thereafter, (4) after the platinum(II) has begun to complex with cellular DNA but before the platinum has permanently and irreversibly damaged renal tubules, e.g. through complexing with SH groups naturally occurring in the renal tubules (which is believed to result in inhibition of water and electrolyte reabsorption in the proximal tubule via coordination of platinum(~I) to the -SH group of a membrane-bound transport enzyme). Presently published research findings, studied with the concepts of this invention in mind tend to suggest that these various ways of defining the preferred and optimum timing of the administration of the dithiocarbamic compounds are generally, even if not precisely, equivalent. The exact timing can depend to a degree on the type of platinum(II) compound, but depends to a greater degree upon the particular dithio-3~

carbamic compound which is selected and the internal processesoccurring within the biological system being treated.
The preferred dithiocarbamic compounds have the structure S
RlR2NCSM
wherein Rl and R2 are the same or different and represent electron-donating lower aliphatic or lower cycloaliphatic rad.icals, and M is selected from the group consistiny of (1) hydrogen, (2) an electro-positive, ionically bonded metal, in which case the remainder of said compound is negative].y charged, and (3) the radical S
-SCNR3R4, R3 and R4 being defined in the same manner as Rl and R2.
The platinum(II) comple~ can be administered in a generally conventional manner, although a single efEective does of platinum(II) or discrate dosages administered several hours apart would be preferred over the continuous courses of intravenous administration typically recommended for the platinum(II) antitumor agents presently in use or under investigation. The route of administration of the dithiocarbamic compounds is preferably tailored to deal with the rapid metabolism or degradation or inactivation of these compounds in acidic media, living biological systems, and other systems in which the dithiocarbarmate functional group (-NCS-) is converted to compounds such a.s carbon disulfide which have no utility in the context of this inventionO
Parenteral (e.g. intravenous or intraperitoneal) administration is ordinarily less subject to excessively rapid degradation of the dithiocarbamic compounds; surprisingly, it has been found that the intravenous route is the most effective on two counts.
First, there appears to be ~ess interference with the desired physiological effects of the platinum(II) Second, the dosage needed to inhibit nephrotoxicity is typically within the range of about 50 to about 400 milligrams per kilogram of body weight, which .is a significant].y lower dosage than would be preferred for the intraperitoneal route.
The following comments pertain to the compositions of choice in intravenous and intraperitoneal administrat.ion of rescue agents:
There are no significant differences in the ingredients used in preparing a solution of the rescue agent for intraperitoneal administration versus intravenous admin:istration. However, solutions of the rescue agent are moderately alkaline and when the solutions are to be administered intravenously, it may be desirable to include an optional buffering agent to maintain the pH at about 8. The solutions are stable at that pH and can be injected at the same pH.

The concentration of the intravenous solutions can vary widely and will depend in part upon the method of administration as well as the amount of platinum anti-cancer drug that has previously been administered.
When the rescue agent is administered intraperitoneally, it is ordinarily given as a massive dose.
However, when the rescue agent is administered intravenously, it is normally dripped into the patient over a period of five-fifteen minutes (e.g. ten minutes). In this regard, cancer patients typically receive large amounts of fluids by intravenous, usually at a rate of approximately 250 ml/hour.
Consequently, it is convenient to use the rescue agent for intravenous administration in the form of a highly concentrated solution which can be administered "piggy-back" with the other unrelated solution that is being administered intravenously.
The intravenous method of administration offers significant advantages in allowing the rescue agent to be used in much smaller quantities than when the same rescue agent is administered intraperitoneally. Current evidence suggest that only about 1/5 of the rescue agent is needed when the rescue agent is administered intravenously rather than intraperitoneally.
5tated another way, this invention is considered to relate to compositions which are useful for inhibiting the ability of the platinum(II) compound to bond strongly or irreversibly to useful en~ymes or sulfhydryl (mercaptan) compounds without inhibiting its ability to complex with cellular DNA.

As noted previously, this invention is not bound by any theory. It is nevertheless theorized that, if a single dose of platinum(II) is administered intravenously on a short-course or almost instantaneous basis, it is likely that platinum(II)-DNA complexes can form within cells (e.g. neoplastic cells) within about an hour after the dose enters the bloodstream. The optimum period of time for DNA
complexing is believed to be more than one hour after platinum administration and more preferably after two hours. As noted previously, the administration o~ the dithiocarbamic compound preferably takes place within six hours of platinum(lI) administration, 1.5-~ hours being the optimum time span allowed for good DNA complexing combined with good inhibition of nephrotoxicity.
Statement of the Invention The compositions of this inven-tion are suitable for use in administration to live mammals (e.g humans) in associa-tion wlth treatment of the mammal by means of a physiologically ; active platinum complex. The composition lncludes a physiologically acceptable carrier and an amount oE a dithiocarbamic compound which will inhibit the ability of the physiologically active platinum complex to bond to substrates in the mammal's body (e.g~ enzymes), without eliminating the desired physiological activity of the platinum complex (e.g.
inhibiting tumor growth). The dithiocarbamic compounds of this composition have the ~ormula RlR2NCSM
wherein Rl and R2 are the same or different and represent electron-donating lower aliphatic or lower cyclo-aliphatic radicals, and M is selected from the group consisting of (1) hydrogen, (2) an electropositive, ionically bonded metal, in which case the remainder of said compound is negatively charged, and (3) the radical -SCNR3R4, R3 and R4 being defined in the same manner as Rl and R2.
These compositions are preferably administered intravenously.
An aqueous solution of dithiocarbamic compound (e.g. the sodium salt, in which case ~=Na) preferably contains a buEfer to maintain the pH of the solution at about 8. Intravenous dosages are usually in the range of 50-400 mg per kg of body weight. If administered 0.5-~ hours after the pla~inum compound, compositions of this invention can ameliorate the harmful side effects of the platinum compound.
Detailed Description The principles of this invention generally relate to a complex situation in which there is a necessity for reversing a platinum(II)/en2yme or platinum(II)/-SH interaction within about six hours of the time that the platinum becomes available for interaction with the enzymes or sulfhydryl groups and perhaps even within four hours of this platinum accessibility.
To further complicate the situatlon, the typica] reason for the accessibility to the platinum is that a chemotherapeutic platinum(II) complex has been administered to an organism or multicellular system, and the desired chemotherapeutic effect would be defeated if the platinum is simply chelated or otherwise rendered inactive before it has had an opportunity - lla ~

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to interact with the targeted substrate. (~he substrate "target" would typically be neoplastic cells, a pathogenic microorganism, a virus, or the like.) These first two conditions can generally be dealt with through careful timing, e.g. of the type described previously. That is, the platinumtII) can be administered first in essentially a single dose followed by administration of the chelating agent or ligand about 0.5 to about 6 hours later. However~ the correct timing is no guarantee of success - either with respect to the chemotherapeutic effect of the platinum or the reversing of platinum/enzyme or platinum/-SH interactions - unless the chelating agent has appropriate properties and can be administered by an appropriate route. If the chelating agent or ligand-forming compound is effective in reversing DNA/Pt(II) bonds, the chemotherapeutic effect of the platinum might be reversed even after apparently stable DNA--Pt(II) complexes have been formed. The route of administration can be important also, since acidic aqueous media, conjugaling sugarsr uronates, glycosides, liver tissue, and other media or agents encountered in living biological systems (and in-vitro systems as well) can inactivate dithiocarbamic toxicity inhibitors of this invention before the inhibitors can bind to the platinum. In experiments with purified DNA, platinum, and alkali metal dialkyldithiocarbamates, it has been found that the dithiocarbamates are sufficiently powerful platinum-binding compounds to dislodge the platinum from D~A/Pt(II) complexes formed in vitro. It would appear from these experiments that Lf~ ~ ~

the dithlocarbamates would be very poor candidates for inhibition of Pt(II) toxicity, since it might be expected from these experiments that the chemotherapeutic e~fect of the platinum would be reversed as easily as the Pt(II)/-SH
complexes.
Stated another way, it would appear from in vitro studies that the difference in mechanism between the beneficial effects and the toxic effects of platinum(II) could not be used to advantage if a dithiocarbamate were selected as the "rescue"
10 agent. This may be one reason why thiourea has generally been considered the most promising "rescue" agent prior to this invention. It is generally believed that the mechanism of anti-cancer activity of platinum(II) involves loss of cis leaving groups on the square planar platinum complex followed 15 by or generally simultaneous with an attack upon the DNA helix in the interior of neoplastic cells. One theory is that the Pt(II)/DNA complexes are characterized by cross-linking of DNA
chains. The toxic effects of the platinum(II) complexes are presently believed to involve complexing with enzymes which 20 occur in various parts of mammals and other complex multicellular organisms, e.g. in the tubule cells and the outer medullary stripe extending into the cortex of the kidney.
Among the signs of platinum(II) toxicity are marked increases in blood urea nitrogen (BUN), weight loss, and diarrhea.
It has now been found that the degradation of dithiocarbamic compounds in acid media or other inactivation reactions may actually be advantageous if the preferred route of administration oE the dithiocarbamic compound is used.
Apparently, the reversal of the DNA/Pt(II) bond observed to occur in vitro with purified DNA does not happen in living multicellular systems. Although this invention is not bound by any theory, it is presently believed that at least two factors may be contributing to the specificity of dithiocarbamic compounds - iOe. their ability to reverse the Pt(II)/-SH bond or other undesired side ef~ects without reversing the Pt(II)/DNA bonds. First, the dithiocarbamic compounds of this invention are believed to be present in vivo as anionic species~ It is generally considered to be more di-fficult for ionic species to penetrate cell membranes, particularly as compared to neutral organic species. Second, and perhaps more important, it is theorized that the dithiocarbamate species which do penetrate cell walls are either degraded or conjugated to form non-chelating products before they can obtain access to the DNA/Pt(II) complexes within the cell. Fortunately, it appears that the biological half life of the dithiocarbamic compounds o~ this invention is long enough to provide reversal of Pt(II)/-SH side effects. At least two parentera] routes of administra~ion have been found to provide adequate dithiocarbamate half lives, these routes being intravenous (i.v.) introduction into the bloodstream of a mammal and introduction into the peritoneal cavity.
To sum up the typical treatment situation as it relates to mammals:

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(a) Internal acidic media (e.g. stomach acid~ and conjugating compounds within the mammal impose severe half-life limitations upon the "rescue" capability of dithiocarbamic compounds.
(b) If the Pt(II)/-SH or Pt(II)/en~yme reactions are not reversed within six hours of Pt(II) administration, it is unlikely that any "rescue" agent will be eEfective, and damage from platinum toxicity may become permanent.
(c) Any "rescue" agent which i5, however, administered tco soon may vitiate the chemotherapeutic eEfect of the platinum(II) complex.
(d) The "rescue" agent should be ineffective with regard to reversing DNA/Pt(II) bonds formed within cellular DNA.
Parenterally-administered dithiocarbamate compounds of this invention have been found to meet these criteria. The preferred routes of administration avoid excessively short half lives for the resclle agents while leaving the chemotherapeutic effects of the platinum substantially intact. Accordingly, to obtain the desired rescue effects via an oral route of administration, it is presently believed that extremely high dosages of dithiocarbamate or, preferably, some other strategem (acid-resistant blocking groups, acid-resistant encapsulation, or the like) would be needed for adequate rescue effec-tsO For example, the pH of the stomach contents of typical non-ruminant mammals is about 4 or less. At this pH, the dithiocarbamate functional group is rapidly converted to carbon disulEide and an amine or other simple nitrogen compound (e.g. an ammonium salt). The pH of blood in mammals i5 typically about 3 units higher, which may partially explain the efficacy of the intravenous route. This inven-tion is not bound by any theory, however, and the reason Eor the extraordinarily high efficacy of the i.v. route is not fully understood. There have been studies in which the chelating behavior of dithiocarbamates has been studied in buffered media, and these studies do not mention any serious half-life problem with the dithiocarbamate functional group.
It is reasonable to conclude that platinum(II) complexes have other useful biological effects besides their apparent ability to bind to DNA in cancer cells. There is evidence that platinum(II) can block the function of the enzyme superoxidedismutase. Pathogenic micxoorganisms can, under appropriate circumstances, be killed by superoxide buildup. If these organisms have an enzyme system which includes superoxidedismutase~ administration of platinum can make the microorganism extreme'y susceptible to a superoxide kill d Whatever the mechanism which may be involved in the use of platinum against microorganisms, there is evidence indicating that platinum compounds are effective against, inter alia, protozoan parasites. Animals suffering from parasites can apparently be cleared of the disease organism with a platinum treatment; however, the same acute platinum toxicity problems as would be encountered in the treatment of cancer occur in this treatment also. In accordance with this invention, - ]6 -`C3~

dithiocarbamic compounds can provide the means for providing a practical platinum treatment for these disease organisms.
The preferred dithiocarbamic compounds used in this invention will now be described in detailO
D iocarbamic Compounds It has long been recogni~ed that dithiocarbamic compounds have an extraordinarily powerEul capability Eor complexing with transition metals. In square planar Pt(II) complexes in particular, the -N-CS-S- func-tional group forms one of the most stable Pt(II) complexes known~ This functional group has a chelating or ligand-forming effect which is almost impossible to reverse with other chelating agents.
Consequently, dithiocarbamic compounds have the ability to substitute for or displace or reverse most other Pt(II) complexes or chelates. Ammonia and amines, for example, are moderately strong ligands in platinum coordinate complexes, but dithiocarbamates can displace them, liberating the free ammonia or amines. Although this invention is not bound by any theory, it is believed that both the thiocarbonyl and the thiol sulphurs of the dithiocarbamic functional group can form s-trong coordinate bonds with platinum. The function of the amido nitrogen in the di-thiocarbamic structure is believed to be generally activating in nature, perhaps due to the unbonded electron pair of the nitrogen. Accordingly, it should follow that electron-donating groups substituted on the amido nitrogen should further intensify the actlvity of the two sulphur atoms.
It would also be e~pected that electron-withdrawing groups - 17 ~

substituted on the nitroyen would decrease the activity of the sulphurs. Theoretical studies by many investigators generally confirm these expectations.
Saturated and non-conjugated unsaturated aliphatic and cycloaliphatic groups are known to have a mild electron-donating effect and are particularly suitable for substitution on the amido nitrogen of the dithiocarbamic structure. "Lower" aliphatic or cycloaliphatic radicals, in the context o~ this invention, are generally considered to be those containing from one to six carbon atoms. These radicals (particularly Cl through C3) do not detract too significantly from solubility of monomeric dithiocarbamic compounds in polar solvents. In addition, these groups do not introduce any acute toxicity aspect to the dithiocarbamic compound. Thus, the preferred dithiocarbamic structure is S
RlR2NCS-wherein Rl and R2 are the same or different and represent electron-donating lower aliphatic or lower cycloaliphatic radicals.
When both Rl and R2 are ethyl, the resulting dithiocarbamic structure has relatively low toxicity and is particularly suitable for administration to living organisms.
For maximum solubility in polar solvents, the preferred dithiocarbamic compounds have -the structure S
RlR2NCSM

wherein R] and R2 are as defined previously, and M is an electropositive, ionically bonded metal.
Structures of this type can dissociate into the corresponding dithiocarbamate ion and an M~ cation in aqueous media. Accordingly, pharmaceutically acceptable cations such as the alkali metal cations (particularly sodium and potassium) are preferred.
Given the proper medium for administration (e.g. a suspending rather than dissolving medium), it is not absolutely essential that monomeric dithiocarbamic compounds be used in this invention. The dimer which has the structure S S
,. .-RlR2NCSSCNR3R4 is known to be cleaved in vivo to form the corresponding monomeric dithiocarbamic compounds. In the dimer structure, R3 and R4 are defined in the same manner as Rl and R2.
In summary, the M in the above-described dithiocarbamic structure can be (1) hydrogen, (2) an electropositive, ionically bonded metal, in which case the remainder of the Fompound is negatively charged, and (3) the second monomer of a dimer.
When Rl, R2, R3 and R~ of the dimer are all ethyl, this tetraethyl species is oEten referred to by its trivial name disulfiram. Disulfiram is commercially available and has been used in the treatment of alcoholism to help the patient remain in a state of self-imposed sobriety. Patients on disulfiram therapy ingesting even small amounts of alcohol experience a highly unpleasant reaction~ Thls alcoholism treatment is carried out by oral administra-tion of disulEiram in tablet form. A disadvantage with disulEiram and similar dimer structures in the context of this invention is their relatively low solubility, particularly in polar solvents. In contrast, diethyldithiocarbamate monomeric salts (e.g. sodium diethyldithiocarbamate) are highly soluble in water, e.g. in molar quantities, and are also soluble in alcohol.
There appears to be no advantage in using the dithiocarbamic acid form of the platinum-bindin~ agents in the context of this invention. These acids generally are soluble in polar solvents such as alcohol, however In alkaline body fluids, they can be neutralized in vivo to form the corresponding carbamate salts.
Dithiocarbamates and related compounds have been reviewed extensively with respect to their chelating ability in a work by G.~. Thorn et al entitled "The Dithiocarbamates and Related Compounds", Elsevier, New York, 1962. In addition, diethyldithiocarbamate has been successfully used in analytical techniques for measuring Pt(II) in urine; see Borch et al~
Analytical Letters B12:917 (1979). Although it will be apparent from Thorn et al that a wide variety of dithiocarbamates have excellent platinum-binding properties, the compounds which appear to be best overall for the purposes S
of this invention are the R2NCS- compounds wherein the R
groups are lower alkyl radicals. It is also known that - 20 ~

diethyldithiocarhamate salts have the ability to reverse the coordination in various coordinate complexes of metals other than platinum. F. W. Sunderman in Ann. Clin. Res 3:182 (1971) and Ann. Clin. and Lab. Sci. 9 1 (1379) has disclosed a treatment for nickel carbonyl poisoning involving the administration of sodium diethyldithiocarbamate (NaDDTC). This invention, on the other hand, is primarily concerned with mitigating the side efEects of platinum compounds deliberately administered to an organism, although the invention does incidentally have utility in the field of treatment of platinum toxicity generally.
Square Planar Platinum Complexes Principally_Relevant to the Context of this_Invention As is well 1cnown in the art oE coordination chemistry, the divalent platinum complexes are square planar rather than octahedral, as in the case of tetravalent platinum.
Although the detailed mechanism by which square planar Pt(II) complexes 0xert a toxic effect upon kidneys is not known, comparison of the chemistry and nephrotoxicity of Pt(II) and Hg(II) suggests a possible mechanism~ Hg(II) also has a high binding a~finity toward sulfhydryl ligands, though not quite the extraordinarily strong affinity of Pt(II). Although this invention is not bound by any theory, it is believed that the brush border of the proximal tubule contains an abundance of protein bound sulfhydryl or mercapto (-SH) groups; see Cafruny et al, J. Pharmacol. Exp Ther. 117:101 (1956). E. J. Cafruny in Pharm. Rev~ 20:89 (1968) postulates for mercury-induced ~ 21 -diureses a mechanism involving reversible inhibition of water and electrolyte reabsorption in the proximal tubule via reversible coordination of Hg(II) to the su]Ehydryl group of a membrane-bound transport enzyme. Because of the striking histopathologic similarities between Pt(II) and Hg(II) toxicity in the rat and because of slower rates of ligand exchange in Pt(II) complexes, Borch et al have suggested that the mechanism for cis-platinum(II) nephrotoxicity in the rat involves a concentration-dependent, substantially irreversible binding of Pt(II) to the protein-bound sulfhydryl groups in the proximal tubule with the resulting inhibition of one or more transport enzymes. See Proc. Natl. ~cad. of Sci. 76:6611 (1979).
Because of the closely analogous coordinate complexing behavior of various Pt(II) compounds, the concepts of this invention have utility whenever a Pt(II) complex is introduced into a biological system such as a complex multicellular organism having kidneys, a digestive system, and similar organs subject to platinum toxicity. Accordingly, the ligands and leaving groups substituted on the square planar complex can vary widely depending upon the reason for platinum administration. If the goal of platinum administration is enzyme inhibition, even the familiar cis--leaving group/cis-diamine structure is not absolutely essential for biolo~ical activity. If, on the other hand, the objective is to attack neoplastic cells with a platinum(II) complex, the most active structures are generally considered to be those of the formula:

L3N\ / xl Pt L3~ x2 wherein Xl and x2 are the same or different and represent anionically ionizable leaving groups, or, taken together, X
and X~ can constitute a cyclic difunctional leaving group such as a cyclic dicarboxylic acid; and L3 and L3 are the same or different and represent the residues of ammine or amine ligands, or, in combination, L3 and L3 together represent 10 the residue oE an aliphatic or cycloaliphatic diamine ligand.
A large number of studies have been carried out on complexes of the type described above. These studies suggest that Xl and x2 are preferably leaving groups with greater lability than ammonia or amines (including monodentate amines 15 and bidentate, difunctional amines). Accordingly, Xl and x2 are typically halogens, hydroxyls, carboxyls, and the like~
For a thorough consideration of suitable cis-Pt(II) structures, see Cancer Treatment Reports ~3:1433, 63:1493, 20 63:14g9, and 63:1475 (1979). The mechanism of action of the cis-platinum(II) type of complex is discussed in the same journal, volume 63, pages 1439-1443 (1979). See also the aforementioned U.S. patents 4,043,587 and 4,]37,248. Of the wide variety of platinum(II~ agents described in these studies, 25 cis-d;chlorodiammineplatinum(II) is presently believed to be the only species on sale in the Uni-ted States for any type of antitumor therapy. ~owever, these studies provide evidence f.~

that other cis-Pt(II) analogs have activity. Furthermore, Pt(II) compounds can have antibacterial activity even iE they do not necessarily have antitumor activity.
According to the literature, preferred antitumor Pt(II) complexes (a) are neutral, (b) contain a pair of cis-leaving groups (generally of intermediate lability, e.g. halogens, oxylates, malonates and other bidentate dicarboxylic acids), (c) two other cis-ligands which are preferably neutral and more or less iner-t; amine systems (particularly as opposed to oxygen or sulphur dentate groups) are more likely to insure antitumor activity. Other transition metals could theoretically be used in place of platinum, but the best results to date have been obtained with platinum compounds. So long as the cis-leaving groups (Xl and x2 in the structural formula previously set Eorth) are better leaving groups than ammonia, amines, and similar nitrogen-containing ligands, the exact nature of Xl and x2 does not appear to be critical. (It is desirable that Xl and x2 form physiologically acceptable anions when displaced from the platinum complex.) Accordingly, in addition to the halogen and hydroxyl and carboxylic leaving groups described previously, activity has been observed with sulato, sulfate, and neutral water molecules.
Of the nitrogen-containing monodentates and bidentates, considerable activity has been shown Eor ammonia, cyclohexanediamine and its derivatives, alkylene diamines (e.g.
ethylenediamine), alkyl-substituted amines, C3 and ~ 24 -C5-cycloalkyl amines, and the like. The trans-analogs appear to be inactive against tumors but can still be active against disease-causing microorganisms~
~fter many decades of studying the various types of cancer, it has been generally established that cancer is not a disease limited to humans. Because of the possible involvement of viruses and/or chemical carcinogens in the environment as at least partially accounting for causes of cancer, various useful and important domestic animals and livestock can be subject to this disease. For cancer research purposes, it has been shown that mice, monkeys, rats, dogs, and other species provide good models for the study of cancer in humans and in mammals generally. With respect to the efficacy and toxic effects of cis-platinum(II) in man, rodents (particularly rats) and dogs provide good models. Platinum(II) nephrotoxicity in the rat is characterized by lesions in the proxirnal -tubules which appear to be closely analogous to the same pathologic changes in man observed in the case of either high-dose or low-dose Pt(II) chemotherapy. In addition, suitable tumors are available for inoculation in rat models. The rat is a less suitable model for investigating the efficacy of orally-administered disulfiram; however, it is also possible to administer disulfiram suspensions parenterally. In any event, parenteral routes of administration are preferred.
The median lethal does (LD50) of cis dichlorodiam-mineplatinum(II) (DDP) Eor F3~ rats has been reported to be 7.5 mg/kg of body weight. In the context of .

this invention, tumor-inhibiting doses of platinum(II) up to approximately the LL)50 level can be administered with as much as 100% survival of all treated animals when a suitable dose of the rescue agent is timely administeredO The platinum(II) complex can be administered by any of the conventional methods, the intravenous method being preferred.
Typical dithiocarbamic compounds used in this invention are Ear less toxic than platinum(II). The dialkyldithiocarbamates, particularly diethyldithiocarbamate sodium or potassium salts appear to have the least toxicity in this family of compounds. Parenteral doses on the order of 1l000 mg/kg are considered generally saEe. In the case of sodium diethyldithiocarbamate (NaDDTC), rescue efficacy is obtained with lower dosage levels in any event. By the i.p.
(intraperitoneal) route, the optimum dosage range appears to be about 50Q-800 mg/kg. Suprisingly, still smaller doses are effective via the i~v. route, e.g. about 50 to about 400 mg/kg, preferably less than 200 mg/kg. Even after an LD50 dose of DDP, an appropriate dose of the rescue agent administered about two hours after the platinum(II) resulted in a sharp drop in nephrotoxicity and gastrointestinal side effects. These results indicate that, not only can these side effects be reduced or substantially eliminated, it is also possible with this invention to relax present limitations on dosages of platinum(II). In humans and other animals, platinum(II) side ef~ects appear to be dose-related, and existing protocols mandate dosages which are below acutely toxic levels~

Nevertheless, chronic nephrotoxicity has still been observed at these relatively low dose le~els. This invention is believed to provide a specific strategy for blocking platinum nephrotoxicity and other side effects in platinum chemotherapy.
The treatment strategy of this invention is believed to be significantly superior to vigorous intravenous hydration combined with mannitol diuresis.
The toxicity of NaDDTC is reportedly low (LD50 is at least 1,500 mg/kg in rats), and there is at least some history oE its use in humans (the treatment for nickel carbonyl poisoning described previously).
In the following non~limiting Examples, toxic side effects of cis-dichlorodiammineplatinum(II) (DDP) were determined through measurements of blood urea nitrogen (BUN) in milligrams per deciliter, weight loss in percent of the animal's weight, observations of any incidence of diarrhea, and microscopic examination o~ kidneys from sacrificed animals.
Urinary excretion of free NaDDTC, total DDTC, and DDTC~glucuronide were determined as described subsequently.
Tumor response was determined by measuring mean tumor diameter in centimeters; see Example 2.
Example 1 Protecting Experimental Animals Against The Toxic E~ect of DDP
("cis-Platinum(II)") With Intraperitoneal NaDDI'C and Disulfiram These experiments were conducted with rats, an accepted model for DDP toxicity. Similar dose related toxic effects have been observed in several animal models and in man.

Maximal plasma and urine platinum levels have been observed shortly after a bolus injection of DDP in man and animals, with a rapid initial clearance followed by a second phase of slow clearance. Plasma and urine concentrations generally decrease to less than 10~ of maximum levels within 1 to 2 hours.
Materials and Methods Male F344 (Fischer) rats (average weight, 150 g) were obtained from the Charles River Breeding Laboratory. They were divided into groups of four rats, placed in methacrylate ca~es, and given National Institutes of Health chow for rodents and water ad lib, for 7 days. Average weight oE the rats was 180 g (range, 160-~00 g) when injected.
Solukions oE DDP (cis-dichlorodiammineplatinum[II]) were prepared immediately prior to injection in isotonic saline (0.9~ NaCl) at a concentration of 1 mg/ml; mannitol (10 mg/ml) was added to duplicate the formulation available for clinical use. l'etraethylthiuram disulfide (disulfiram) was obtained from Sigma Chemical Co., St. Louis, Missouri. Sodium DDTC was prepared according to the procedure of Klopper and van der Kerk, Rec. Trav. Chim. 70:917 (1951); immediately prior to injection, it was dissolved in sterile water at a concentration of 100 mg/ml. Sodium bicarbonate was prepared in sterile water at a concentration of 50 m~/ml. All injections were carried out under brie~E ether anesthesia.
Rats in groups of 8-16 were injected intravenously with DDP at a dose of 7.5 mg/kg (the median lethal dose [LD50]); see Ward et al, Toxicol. App. Pharmacol. 38:535 (1976). The rats were then randomly divided into two groups;
at times from 0 to 6 hours after injection of DD~, one group was injected intraperitoneally with NaDDTC (500 or 750 mg/kg), and the other group was injected intraperitoneally with sodium bicarbonate (370 mg/kg) as a control. One group of rats was given only NaDDTC, in a dose of 750 mg/kg intraperitoneally, to serve as a control for the effects of NaDDTC. In one experiment, blood was obtained from the tail vein for serial daily BUN (blood urea nitrogen) determinations according to Foster et al, ClinO Chem. 17:921 (1971). Otherwise, weight and .
~UN were determined at 5 days after injection, reportedly the time of maximal observed toxicity. Evidence of gastrointestinal toxicity was obtained qualitatively by noting the presence or absence of diarrhea 3-5 days after injection.
Disulfiram was administered to two groups of rats in lieu of NaDDTC, as described subsequently.
Randomly selected animals were sacrificed at 5 days aEter injection for study of histopathologic changes in the l~idney and to note the presence or absence of hemorrhagic enteri-tis. Kidneys were removed, placed in Zenker's fixative, embedded in paraffin, sectioned at 6 um, and stained with hematoxylin and eosin~
Resul-ts Sodium DDTC, at doses of 500 and 750 mg/kg, was given at times ranging from 30 minutes before to 6 hours after administration of DDP; see T~BLE 1, which follows. The rats that recei~ed NaDDTC alone maintained normal BUN levels throughout the 2-week period but experienced a mean weight loss of 6% at day 5; by 2 weeks, however, a mean weight gain of 6~
was observed. The control animals, which received DDP at 7.5 mg/kg without rescue, experienced a mean wei~ht loss of 21~ at 5 days and had a mean BUN level of 234 mg/dlO Serial BUN and body weight determinations in both control and rescued animals confirmed that maximal BUN and weight loss occurred on day 5.
Survivors generally showed recovery of both weight and BUN from these extreme levels. Diarrhea was observed in 21 or the 22 animals examined for ito Necropsy revealed a distended membranous small intestine filled with hemorrhagic Eluid in every animal examined. Sections of the kidney revealed a pale zone oE extensive necrosis and degeneration of tubule cells in the outer medullary stripe extending into tlle corte~.
Marked reduction in BUN and weight loss were noted when NaDDTC was administered between 1 and ~ hours aEter DDP, but results Eor the 6-hour rescue time suggested only minimal rescue efficacy (if any). Diarrhea was not observed in any of these rescued animals. Necropsy revealed a grossly normal small intestine; kidney sections showed a barely discernible pale band of mild tubule degeneration in the outer 20ne of the outer medullary stripe. When NaDDTC was administered immediately after DDP ttime = 0 hour), a significant decrease in weight loss was noted without reduction of BUN levels~
Rescue 6 hours after DDP administration, however, failed to demonstrate significant reduction either in BUN or weight loss, and two of the five animals in this group were noted to have diarrhea Platinum excretion kinetics were measured in four animals by rneasuring urinary platinum levels every 30 minutes for 4 hours and then every 2 hours for an additional 12 hours.
Urinary platinum concentration declined -to < 10% of maximal concentration within 1.5 hours and > 95% of the platinum excreted by the kidneys had appeared in the urine by this time.
In one experiment, disulfiram was administered to two groups of rats at a dose of 2 y/kg via stomach tube 30 minutes before and 30 minutes after DDP. Fifty percent of the aminals in each group died before day 5, with grossly hemorrhagic fluid-filled intestine noted on necropsy. Weight loss and BUN
levels in the survivors were highly variable (BUN, 55-1~0 mg/dl)~
These results are believed to demonstrate the salutary effects of NaDDTC rescue of renal function and pathology after a toxic dose of cis-platinum and to strongly suggest a beneficial effect upon gastrointestinal toxicity as well.
For NaDDTC, the rat model appears to be a good oneO
In any event, it is believed that all species initially present free NaDDTC to the kidney tubule; its site and rate of decomposition depend upon site and rate of urine acidification.
On the basis of these data and our resu]ts, we suggest the following rationale for DDP toxicity and NaDDTC
rescue. At high plasma and urine platinum concentrations, binding occurs to sulfhydryl groups of the renal tubule;
maximal platinum accumulation occurs at 30-60 minutes. Sodium DD~C administered 30 minutes prior to or concurrent with DDP is rapdily metabolized be~ore platinum accumulates, and NaDDTC
concentrations af~er 1 hour are inadequate to remove bound platinum. Rescue between 45 minutes and 4 hours is particularly effective because NaDDTC concentration in the tubular fluid is adequate for platinum chelation and removal.
The minimal rescue at 6 hours presumably results from platinum-induced irreversible damage having occurred prior to rescue. Although inhibition of gastrointestinal toxicity generally parallels that observed ~or nephrotoxicity, the beneficial results of concurrent administration suggest that gatrointestinal toxicity may be more responsive to early rescue.
The variability of results with disulEiram do not negate its efficacy as a rescue agent, but merely suggest that careful technique is needed for the most e~fective administration.

-Example 2 Exarnple 1 is believed to demonstrate that intraperitoneal ~ip) administration of NaDDTC in doses of 500-750 mg/kg would afford protection from the nephrotoxic effects of DDP at doses as high as 8 mg/kg. The purpose of this Example is to test intravenous (i.v.) as well as ip administration and also to test the effect of NaDDTC on DDP
efficacy. Rat mammary tumor 13762 model was selected to determine the effect of NaDDTC on inhibition of tumor growth by DDP. This tumor model is unusual in that spontaneous relapse at the original site occurs approximately 15 days after DDP
administration in 25-75% of animals. Although initial tumor response to 2, 4, and 8 mg/kg DDP was identical with or without NaDDTC rescue, local recurrence commenced earlier and tumors grew more rapidly in those animals receiving NaDDTC at intraperitoneal doses of 750 mg/kg.
Intravenous administration was explored in an attempt to deliver larger quantities of free DDTC anion to the likely site of toxicity in the renal tubule; urinary excretion of DDTC
was monitored as a means of estimating changes in tubular levels of free DDTC. The standard assay for DDTC anion utilizes a spectrophotometric determination following reaction with cupric ion to form the coloured Cu(DDTC)2 complex.
Unfortunately, the affinity of cupric ion for sulfur ligands is such that this metal ion will catalyze the decomposition of the DDTC glucuronide and therefore will not discriminate between free and conjuga-ted DDTC. Ferric ion does react selectively with the free ligand, thereby providing a convenient assay for both free and total DDTC in urineO
According to J. H. Stromme in Blochem. Parmacol., 14:393 (1965), DDTC is rapidly conjugated in the liver. It was -theorized that i.v. administration should therefore be more effective than the oral or intraperitoneal route for delivery of free DDTC to the kidney. Acetazolamide was also investigated as a means for increasing the pH at potential sites of degradation of the DDTC in the kidney. The combination of DDTC and acetazolamide did result in significant increases in renal excretion of DDTC as expected, even when the NaDDTC dose was reduced by 80%. Notwithstanding this increase in urinary DDTC levels, the combination DDP-DDTC-acetazolamide was clearly more toxic to rats than DDP-DDTC alone.
Accordingly, this Example will focus on the tumor growth studies and upon i.v. administration without acetazolamide.
Materials and Methods -Female F344 (Fischer) rates, initial weight 100-150 g, were obtained from the Charles River Breeding Laboratory, Wilmington, Massachusetts. They were housed in methacrylate cages and given Purina rat chow and water ad libitum for at least one week. Mean weight of the rats were 150 g at the onset of experiments unless otherwise noted.
Solutions of cis-dichlorodiammineplatinum(II) (DDP) were prepared immediately prior to injection in normal saline (0.9% NaCl) at a concentration of 0.2-1.0 mg/ml. Solutions of sodium diethyldithiocarbamate (NaDDTC) (Sigma Chemical Co., St.

Louis, Missouri) were prepared immediately before use at a concentration in mg/ml e~ual to the dose expressed in mg/100 g;
thus, injection volumes were identical at all dose levels.
Mammary Tumor 13762 was obtained in the form of an implanted tumor in a female F344 rat. All intravenous injections were carried out under brief ether anesthesiaO
Tumor inoculation was carried out as follows: two rats bearing tumors having a mean diameter of 2.5-3.5 cm were sacrificed using ether anesthesia. The tumors were excised immediately, Einely minced, combined, and resuspended in 20-40 ml of normal saline. This suspension was filtered through a gauze pad to remove coarse pieces oE tissue and the resulting suspension inoculated subcutaneously (0.2-0.5 ml/injection) into the left flank of each rat. Tumors were palpable within 7 days in ~ 98~ of inoculated animals and generally reached a mean diameter of 2.5-3.5 cm within 10-14 days.
Comparative tumor respcnse experiments were carried out by inoculating randomly selected control and rescue groups with tumor as described above. On day 10, DDP at the appropriate dose was administered intravenously to both control and rescue groups. Two hours after DDP administration, the rescue group was treated with NaDDTC at a dose of 750 mg/kg given intraperitoneally (ip) or 100 mg/kg given intravenously (iv.) Tumor size was determined by measuring the longest and shortest diameters with a calipers and recording the arithmetic average. The rats were monitored for 50 days after tumor inoculation or until tumor size exceeded 4 cm. Comparative nephrotoxicity experiments were carried out as descrlbed in Example 1. In those experiments using acetazolamide, this drug was administered in a dose of 10 mg/kg intraperitoneally 30 S minutes prior to administration of DDP, and rescue was carried out 3 hours aEter administration of DDP.
Fxcretion of Eree and conjugated NaDDTC in the urine of rats was measured as follows. NaDDTC was administered in selected doses via intraperitoneal or intravenous injection.
Rats were then placed in metabolic cages and urine was collected and analyzed at 30 minute intervals, Urine samples (0.1-5.0 ml) were added to 2 ml of a solution containing ferric nitrate (20 mM) and sodiùm citrate ~200 mM). The dark Fe-DDTC)3 complex was extracted into chloroform (4 ml) hy vortexing for 5 minutes. The mixture was chilled, centrifuged for 1 minute, and the chloroform layer separated. To this chloroform solution was added saturated aqueous cupric sulfate (2 ml), and the mixture was vortexed for 5 minutes, chilled, and centrifuged for 1 minute. The chloroform solution was separated and the Cu(DDTC)2 absorbance measured at 435 nm.
Free DDTC was determined by comparison of absorbance to a standard curve. Total DDTC was determined by addition of 0~05-1.0 ml of urine to 3 ml of saturated cupric sulfate followed by incubation at 45 for 30 minutes. The resulting Cu(DDTC)2 complex was extracted into chloroform and analyzed as described above. DDTC-glucuronide excretion was determined by subtraction of free Erom total DDTC.

~esults DDP was administered on day 10 after injection of tumor cells in doses of 2, 4, and 8 mg/~g to duplicate groups of 8 rats (mean weight 12S g) at each dose level. NaDDTC
rescue was carried out 2 hours after DDP administration in one group at each dose level usiny an intraperitoneal dose of 750 mg/ky. At a DDP dose of 2 mg/kg without rescue, mean tumor size diminished progressively until day 24, when 2/8 rats were tumor free and 6/8 rats bore tumors which reached mean minimum diameter of 1.6 cm. At day 30, mean tumor diameter in these six rats had increased to 2.4 cm. Treatmen-t with 2 mg/kg DDP
followed by 750 mg/kg DDTC 2 hours later gave an initial response identical to that of the unrescued group;
disappearance of tumor was not observed in this rescued group, however, and mean minimum tumor diameter reached 1.2 cm at day 21 with relapse to a mean tumor diameter of 3.0 cm at day 30.
The rescue thus leads to an identical initial response but with earlier onset of relapse and more rapid subsequent tumor growth than in the absence of rescue. Qualitatively similar results were obtained at DDP doses of A and 8 mg/kg. In the latter case, however, 3/8 rats died as a result o DDP nephrotoxicity and 3/8 were tumor-free by day 28 in the unrescued group; with DDTC rescue there were no deaths and 1/8 was tumor-free by day 28.
When NaDDTC (500 m~/kg) was administered intraperitoneally to rats, total DDTC excreted by the kidneys within 2 hours represented 18-20~ of the dose yiven. Of this ~ 38 -DDTC analyzed in the urine, ~0.1~ of the initial dose was present as the free ligand; the remainder was the S-glucuronide conjugate. Administration of DDTC as an intravenous bolus of 100 mg/kg increased renal free DDTC excretion in the first 30 minutes by five- to tenfold over that observed with a 500 mg/kg intraperitoneal dose.
Comparison of low-dose intravenous vs. high-dose intraperitoneal DDTC rescue showed that protection against nephrotoxicity was essentially equivalent for both routes. DDP
(6 mg/kg intravenously) was administered to 3 groups of 8 rats each. The control group received no further treatment, the intravenous group received 100 mg/kg NaDDTC intravenously, and the intraperitoneal group received 750 mg/kg NaDDTC
intraperitoneally 2 hours after DDP. Weight loss on day 5 was similar in the three groups tll, 14, and 9%, respectively);
diarrhea was noted in 1/8 rats in the control group but was not observed in the intravenous or intraperitoneal groups. Day 5 BUN's for the control, intravenous, and intraperitoneal groups were tmean - SEM) 92 + 15, 43 -~ 5, and 73 ~ 4, respectively._ Kidney sections Erom the control group revealed a zone of moderate necrosis and degeneration at the corticomedullary junction similar in type but to a lesser degree than observed in Example 1 at DDP doses of 8 mg/kg. Sections from the intravenous and intraperitoneal rescue groups were very similar and showed mild hydropic changes with occasional evidence of degeneration a ~2~ 36~

Finallyr tumor responses to DDP in the absence of rescue and in the presence of low-dose intravenous and high-dose intraperitoneal rescue were compared. DDP (2 mg/kg intravenously) was administered on day 10 after tumor inoculationO The control group (n = 8) received no further treatment; the intravenous (n = 8) and intraperitoneal (n =11) groups received NaDDTC 2 hours after DDP in doses of 100 mg/kg intravenously and 750 mg/kg intraperitoneally, respectively.
Tumor response in the intraperitoneal rescue group was ~ualitatively similar to that described previously; minumum tumor diameter (1.3 cm) was reached on day 23 with relapse occuring in 9/11 rats to a mean tumor diameter of 2.2 cm by day 30 (data not shown). Tumor response in the control and intravenous rescue groups, however, were generally equivalent in all respects. Initial response was identical in both groups; relapse was observed in 2/8 rats in each group between days 25 and 30, with the other rats remaining essentially free of tumor through day 50 when the study was terminated.
In short, when 2 mg/kg is the i.v. DDP dose, and 100 mg/kg is i.v. rescue dose, no adverse effects of NaDDTC
administration on tumor response to DDP were observed. It appears from these data that sodium diethyldithiocarbamate can be adminis-tered intravenously in doses which effectively inhibit platinum-induced nephrotoxicity without deleterious efects on tumor response. The reason for the superiority of the i.v. route of NaDDTC administration over the other parenteral route used in this Example (the ip route) is not 3~

understood at this time. The ip route of rescue administration does not seem to have any significant adverse effect upon initial tumor response, but locally recurring tumors recur earlier and grow rnore rapidly when compared to the results in the DDP/i,v. rescue experiments.

Claims (12)

WHAT IS CLAIMED IS: .

1. A composition suitable for use in administration to a live mammal in association with treatment of the mammal for a neoplastic growth by means of a physiologically active platinum (II) complex, the composition being useful for inhibiting the toxicity of the platinum(II) complex on the mammal, comprising a therapeutically effective dosage of the platinum-binding compound R1R2N?SM
wherein R1 and R2 are the same or different and represent electron-donating lower aliphatic or lower cyclo-aliphatic radicals, and M is selected from the group consisting of (1) hydrogen, (2) an electropositive, ionically bonded metal, in which case the remainder of said compound is negatively charged, and (3) the radical -S?NR R4 , R3 and R4 being defined in the same manner as R1 and R2 and a physiologically acceptable carrier.

2. A composition according to claim 1 wherein said platinum-binding compound is R5R6 N?S-M+
wherein M+ represents a pharmaceutically acceptable cation, and - Page one of Claims -R5 and R6 are the same or different and represent lower alkyl groups.

3. A composition according to claim 2 wherein said platinum-binding compound is an alkali metal diethyldithio-carbamate.

4. A composition according to claim 1 wherein said platinum (II) complex is a compound of the formula:

wherein X1 and x2 are the same or different and represent anionically ionizable leaving groups, or, taken together, X1 and x2 can constitute a cyclic difunctional leaving group; and L3 and L'3 are the same or different and represent the residues of ammine or amine ligands, or, in combination, L3 and L'3 together represent the residue of an aliphatic or cycloaliphatic diamine ligand.

5. A composition according to claim 1 wherein the composition is suitable for intraperitoneal administration to the said mammal.

6. A composition according to claim 1 wherein the composition is suitable for intravenous administration to said mammal.

- Page two of Claims -

7. A composition according to claim 6 wherein said dosage of the platinum-binding compound ranges from about 50 to 400mg per kg of body weight of said mammal.

8. A composition according to claim 5 suitable for non-oral administration to said mammal 0.5 hours to 6 hours after treatment of said mammal with said platinum (II) complex.

9. A composition according to claim 6 suitable for non-oral administration to said mammal 0.5 to 6 hours after treatment of said mammal with said platinum(II) complex.

10. A composition according to claim 7 suitable for non-oral administration to said mammal 0.5 hours to 6 hours after treatment of said mammal with said platinum(II) complex.

11. A composition according to claims 9 or 10 wherein said treatment of the mammal for a neoplastic growth consists of intravenous administration of a tumor-inhibiting dose of the compound:
wherein X1 and x2 represent anionically ionizable leaving groups or, taken together, can constitute a cyclic dicarboxylic acid; and R represents hydrogen or the residue of an organic ligand, or both R groups in combination can constitute the residue of an aliphatic or cycloaliphatic diamine ligand - Page three of Claims -and said platinum-binding compound is the water soluble compound wherein M+ represents an alkali metal cation, and R5 and R6 are the same or different and represent lower alkyl radicals.

12. A composition suitable for use in association with cis-dichlorodiammineplatinum (II) used in the treatment of neo-plastic growths in mammals, the composition being useful in the binding of cis-dichlorodiammineplatinum (II), comprising the sodium salt of diethyldithiocarbamate and physiologically acceptable carrier suitable for intravenous administration to the mammal within about 0.5 hours to 6.0 hours after treatment of the mammal with cis-dichlorodiammineplatinum (II).

- Page four of Claims -