Cancer Treatment
Revielvs (1990)
17, 139-142
Pharmacological platinum-induced Sergio
interventions toxicity
to reduce
Tognella
Research Center, Boehringer
Mannheim
Italia,
Monza,
Milan,
Itab
Cis-diamminedichloroplatinum (II) or cisplatin is one of the most important anticancer drugs of the last 20 years. The discovery of its antitumoral activity came from a perceptive intuition of Rosenberg (8) studying the effects of an electric field on growing cells. The first clinical results were very promising, but the compound was nearly discarded because of its unusual and very severe kidney toxicity. A major therapeutic advance was the discovery that simple, but adequate hydration of the patient could markedly decrease the nephrotoxicity ofcisplatin without interfering with its anticancer activity. Even better were the results using hypertonic saline as the drug vehicle together with extensive hydration. As a consequence, the possibility of administering cisplatin at higher doses with acceptable toxicity led to more extensive clinical trials in different types of tumours and in a variety of combinations with other anticancer agents. As a result cisplatin is now the drug of choice in multi-drug regimens for the treatment of non-seminomatous testicular cancer and of ovarian cancer and it is useful in the treatment of many other solid turnouts (e.g. head and neck, bladder, lung, sarcomas, lymphomas), usually as part of combination chemotherapy. Cisplatin in water reacts immediately by exchange of the labile chlorides for water or hydroxyl ions. The aquation reaction of cisplatin is highly dependent on chloride levels. In plasma, or in high chloride fluids, the neutral dichloro complex will predominate whereas intracellularly, where the chloride ion concentrations are very low, the aquated species will predominate. The aquated complexes are very reactive and are easily replaced by a variety of nucleophiles. The cisplatin antitumour effect is mediated by reaction with DNA, the N-7 position of guanine being the most reactive site. There is an initial formation of mono-adducts and then a rapid intra-stand cross-linking, responsible for the cisplatin cytotoxicity. These reactions are merely mentioned here because of their importance in understanding the possible mechanism of action of some ‘chemoprotectors’. It ought also to be mentioned here that Carboplatin, a less toxic analog of cisplatin now on the market, forms the same platinum-DNA adducts as cisplatin but with different kinetics of DNA binding. The full anticancer activity of cisplatin and Carboplatin have yet to be explored if and when their severe dose-limiting toxicity can be overcome. Nephrotoxicity is the doselimiting toxicity of cisplatin at conventional doses (up to 120 mg/m’) and neurotoxicity is the toxicity limitation at high doses (160-200 mg/m*) (Table 1). The dose-limiting toxicity of Carboplatin, althou,gh less nephrotoxic than cisplatin, is myelosuppression. 030557372/90/2&3139
to4
s03.00/0
0 139
1990 Academic
Press Limited
140
S. TOGNELLA Table
1.
Major
clinical
toxicities
of cisplatin”
Gastrointestinal Nausea and vomiting Renal Polyuria BUN and creatinine Tubular necrosis Hematological Anemia, leukopenia, Neurological Paresthesiae Loss of proprioception Gait disturbances Otological Tinnitus Loss of high frequency “Neurotoxicity dose regimens.
increase
thrombocytopenia
and vibratory
hearing;
is the dose-limiting
sensation
deafness toxicity
of high-
A variety of techniques and agents has been proposed to overcome the major toxicities of platinum complexes (Table 2) and to improve their therapeutic indices. Nausea and vomiting are usually treated with limited success with various drugs (e.g. cannabinoids, high-dose metoclopramide and dexamethasone). Very recently good results have been reported with 5-HT, antagonists such as ondansetron and granisetron. Protection against kidney toxicity has been achieved by vigorous parenteral hydration and forced diuresis. Even with this strategy however severe nephrotoxicity develops for doses higher than 100-l 20 mg/m’. Following the experimental data of Litterst (5), 0~01s (7) was able, by administering cisplatin in hypertonic (3%) saline and maintaining extensive hydration, to reach 200 mg/m’ per cycle without important nephrotoxicity. With this high dosage the dose-limiting toxicity was a very severe peripheral neuropathy and ototoxicity. Many pharmacological attempts to decrease cisplatin toxicity have been made utilizing a number of thiol compounds as potential chemoprotectors (see Table 2). One of the best studied is diethyldithiocarbamate (DDTC) which seems able to remove platinum from mono-guanine adducts, but is completely unreactive toward the cisplatinhis-guanine adducts (1). It seems possible that due to these reactions DDTC has the unique ability to ‘rescue’ normal tissues from platinum toxicity even ifadministered after cisplatin treatment. Unfortunately, DDTC does not protect the bone marrow and has severe acute side-effects that make its clinical use very difficult. The major side-effects are severe Table
2.
Methods toxicity turnour
and of drugs
agents to reduce platinum anti-
Hydration Hypertonic saline + hydration Diethyldithiocarbamate (DDTC) Thiosulfate WR-272 1 ORG.2766 Glutathione
PLATINUM-INDUCED
diaphoresis,
profound
uneasiness
and anxiety,
TOXICITY
REDUCTION
chest discomfort,
141
hypertension
and flushing
(9). Thiosulfate is another thiol compound that has been shown experimentally to be able to reduce cisplatin-induced nephrotoxicity but only when administered prior to cisplatin. It is ineffective on other systemic toxicities. Moreover, thiosulfate can interfere with the antitumour activity ofcisplatin. For this reason it has been proposed for the so-called ‘tworoute chemotherapy’ that is for loco-regional treatment (e.g. intraperitoneal cisplatin) with systemic protection (4). WR-2721 is an aminothiol, used as a radioprotector which also shows interesting selective protection against the toxicity of alkylating agents and cisplatin. The basis for the selectivity of WR-2721 is not well understood but it seems likely to be due to its hydrolysis to the free thiol (WR-1065) which is selectively taken up by normal cells in comparison with cancer cells. It is effective only when administered just prior to cisplatin. Its major side-eflect is hypotension (especially with high doses; 910 mg/m’) but nausea, vomiting, flushing and somnolence have also been reported. The preliminary clinical results of the combination of cisplatin (up to 150 mg/m’) with WR-2721 are promising, even though some neuro- and ototoxicities have been observed (3). Caution is however required since WR-272 1 is a potent inactivator of y-glutamylcysteine synthetase, thus reducing hepatic glutathione, which could result in an increase of the toxicity of a variety of free radical generating agents ( 10). ORG.2766, an ACTH, 9 analog devoid of the hormonal effect of ACTH, is a neurotrophic peptide that is able to experimentally protect animals from the neurotoxicity of cisplatin. The mechanism of action is not clear but it seems not to be related to an interference with the cisplatin-DNA binding in dorsal root spinal ganglia (11). The preliminary clinical results are encouraging. One compound which has been extensively studied and whose modulation has been shown to alter the cell response to a variety of anticancer agents, is glutathione (GSH). A variety of approaches have been tried with the object of manipulating the GSH level within tumour cells in order to increase their susceptibility to antitumour agents or to increase the protection of normal cells. Buthionine sulfoximine, for example, a potent inhibitor of y-glutamylcysteine synthetase, has been used to decrease the cellular level of GSH, especially for resistant tumour cells whose resistance could be linked to an increase of GSH (6). The results so far achieved are inconsistent, with the toxicity sometimes being increased more than the cell susceptibility. Another approach has been to administer high-dose GSH intravenously with the aim of ‘activating’ the y-glutamyl cycle to gain better protection of cells rich in transpeptidase (kidney, bladder) and to simultaneously increase the efficacy of anticancer compounds through the activation of transport mechanisms. The uptake of extracellular GSH by most tissues (and by cancer cells) is undetectable or very low and a direct reaction of GSH with drugs such as cisplatin in plasma is very unlikely. The results of experimental studies, however, showed not only a good protection against the toxicity of cisplatin, cyclophosphamide and ifosfamide, but also some improvement of antitumour activity of cisplatin ( 12, 13). Since the first clinical trials confirmed the good protection against cisplatin and cyclophosphamide-induced toxicities, a trial in patients with advanced bulky ovarian cancer treated with five cycles (one every 3-4 weeks) of GSH (1500 mg/m’ i.v., 15 min before cisplatin) plus high-dose cisplatin (40 mg/m’ x 4 days) plus cyclophosphamide (600 mg/m* on day 4) and with ‘normal’ hydration (2000 ml of saline per day) was performed at the Instituto Nazionale Tumori in Milan. ‘I’he first results of this pivotal trial were
142
S. TOGNELLA
recently communicated (2) and are very impressive. No nephrotoxicity was seen, even with such moderate hydration, myelosuppression was mild and neurotoxicity, never associated with motor dysfunction, was a frequent but not severe (grade l-2) and reversible cumulative side-effect after four to five cycles. Fifty-one patients so far are evaluable. The overall response rate is 82%, with 59% complete responses. Even in the group of patients with a tumour size larger than 5 cm after the surgical operation a complete response was seen in 44%. The excellent protection against the toxicities (including neurotoxicity) of cisplatin in high-dose regimens, and the lack of any intrinsic toxicity of glutathione make the latter a good candidate for clinical trials which seek to test the possibility of increasing the therapeutic index of cisplatin.
References 1. Bodenner,
D. L., Dedon,
P. C., Keng,
P. C. & Borch,
diamminedichloroplatinum (II)-induced inhibition. Cancer Res. 46: 2745-2750. 2. Bohm, S., di Re, F., Oriana, S., Spatti, High dose cisplatin with glutathione Meeting 3. Glover,
International D., Grabelsky,
Gynecological S., Fox, K.,
cytotoxicity,
R. F. (1986) DNA
Effect
cross-linking,
ofdiethyldithiocarbamate
on cZS-
and y-glutamyl-transpeptidase
G. B., Tedeschi, M., Tognella, S., Veronesi, P. & Zunino, F. (1989) protection in patients with bulky advanced ovarian cancer. 2nd
Cancer Society, Toronto, 1989 (abstract). Weiler, C., Cannon, L. & Glick, J. (1989)
Clinical
trials
of WR-2721
and &platinum. Znt. J. Radial. Oncol. Biol. Phys. 16: 1202-1204. 4. Kobayashi, H., Hasuda, K., Aoki, K., Kuroiwa, T., Taniguchi, S. & Baba, T. (1989) “Two-route chemotherapy” using cis-diamminedichloroplatinum (II) and its antidote, sodium thiosulfate, combined with angiotensin II is effective against peritoneally 141-147. 5. Litterst, C. L. (1981) Alterations in the toxicity of platinum as a function of NaCl concentration
disseminated
cancer
in rats.
Cancer Chemother.
of&-dichlorodiammineplatinum in the vehicle of administration.
Pharmacol.
24:
II and in tissue localization
Toxicol.
Appl. Pharmacol.
61: 99-108. 6. Mitchell, J. B. (1988) Glutathione modulation and cancer treatment. ISI Atlas Sci. Pharmacol. 2: 155-160. 7. Ozols, R. F., Corden, B. J., Jacob, J., Wesley, M. N., Ostchega, Y. & Young, R. C. (1984) High-dose cisplatin in ovarian cancer. Ann. Int. Med. 100: 19-24. 8. Rosenberg,
Inhibition
of cell division
products from a platinum electrode. Nature 205: 6988699. 9. Rothenberg, M. L., Ostchega, Y., Steinberg, S. M., Young, dose carboplatin with diethyldithiocarbamate chemoprotection
B., van
Camp,
L. & Krigas,
T. (1965)
R. C., Hummel, in treatment
in Escherichia
coli by electrolysis
S. & Ozols, R. F. (1988) Highofwomen with relapsed ovarian
cancer. J. N&l. Cancer Inst. 80: 1488-1492. 10. Shor, N. F. (1988) Mechanism of synergistic toxicity of the radioprotective agent WR-2721, and 6hydroxydopamine. Biochen. Pharmacol. 37: 1751-1762. 11. Terheggen, P. M. A. B., van der Hoop, R. G., Float, B. G. J. & G’ 1sp en, W. H. (1989) Cellular distribution of cis-diamminedichloroplatinum(II)-DNA b’m d’ m g in rat dorsal root spinal ganglia: effect of the neuroprotecting peptide ORG.2766. Toxicol. Appl. Pharmacol. 99: 334-343. 12. Zunino, F., Pratesi, G., Micheloni, A., Cavalletti, E., Sala, F. & Tofanetti, 0. (1989) reduced glutathione against cisplatin-induced renal and systemic toxicity and its influence activity 13. Zunino, against 111.
of the antitumor drug. Chem. Biol. Interact. 70: 899101. F., Tofanetti, O., Besati, A., Cavalletti, E. & Savi, G. (1983) cis-dichlorodiammine platinum (II)-induced nephrotoxicity
Protective effect of on the therapeutic
Protective effect ofreduced glutathione and lethal toxicity. Tumori 69: 1055
Revielvs (1990)
17, 139-142
Pharmacological platinum-induced Sergio
interventions toxicity
to reduce
Tognella
Research Center, Boehringer
Mannheim
Italia,
Monza,
Milan,
Itab
Cis-diamminedichloroplatinum (II) or cisplatin is one of the most important anticancer drugs of the last 20 years. The discovery of its antitumoral activity came from a perceptive intuition of Rosenberg (8) studying the effects of an electric field on growing cells. The first clinical results were very promising, but the compound was nearly discarded because of its unusual and very severe kidney toxicity. A major therapeutic advance was the discovery that simple, but adequate hydration of the patient could markedly decrease the nephrotoxicity ofcisplatin without interfering with its anticancer activity. Even better were the results using hypertonic saline as the drug vehicle together with extensive hydration. As a consequence, the possibility of administering cisplatin at higher doses with acceptable toxicity led to more extensive clinical trials in different types of tumours and in a variety of combinations with other anticancer agents. As a result cisplatin is now the drug of choice in multi-drug regimens for the treatment of non-seminomatous testicular cancer and of ovarian cancer and it is useful in the treatment of many other solid turnouts (e.g. head and neck, bladder, lung, sarcomas, lymphomas), usually as part of combination chemotherapy. Cisplatin in water reacts immediately by exchange of the labile chlorides for water or hydroxyl ions. The aquation reaction of cisplatin is highly dependent on chloride levels. In plasma, or in high chloride fluids, the neutral dichloro complex will predominate whereas intracellularly, where the chloride ion concentrations are very low, the aquated species will predominate. The aquated complexes are very reactive and are easily replaced by a variety of nucleophiles. The cisplatin antitumour effect is mediated by reaction with DNA, the N-7 position of guanine being the most reactive site. There is an initial formation of mono-adducts and then a rapid intra-stand cross-linking, responsible for the cisplatin cytotoxicity. These reactions are merely mentioned here because of their importance in understanding the possible mechanism of action of some ‘chemoprotectors’. It ought also to be mentioned here that Carboplatin, a less toxic analog of cisplatin now on the market, forms the same platinum-DNA adducts as cisplatin but with different kinetics of DNA binding. The full anticancer activity of cisplatin and Carboplatin have yet to be explored if and when their severe dose-limiting toxicity can be overcome. Nephrotoxicity is the doselimiting toxicity of cisplatin at conventional doses (up to 120 mg/m’) and neurotoxicity is the toxicity limitation at high doses (160-200 mg/m*) (Table 1). The dose-limiting toxicity of Carboplatin, althou,gh less nephrotoxic than cisplatin, is myelosuppression. 030557372/90/2&3139
to4
s03.00/0
0 139
1990 Academic
Press Limited
140
S. TOGNELLA Table
1.
Major
clinical
toxicities
of cisplatin”
Gastrointestinal Nausea and vomiting Renal Polyuria BUN and creatinine Tubular necrosis Hematological Anemia, leukopenia, Neurological Paresthesiae Loss of proprioception Gait disturbances Otological Tinnitus Loss of high frequency “Neurotoxicity dose regimens.
increase
thrombocytopenia
and vibratory
hearing;
is the dose-limiting
sensation
deafness toxicity
of high-
A variety of techniques and agents has been proposed to overcome the major toxicities of platinum complexes (Table 2) and to improve their therapeutic indices. Nausea and vomiting are usually treated with limited success with various drugs (e.g. cannabinoids, high-dose metoclopramide and dexamethasone). Very recently good results have been reported with 5-HT, antagonists such as ondansetron and granisetron. Protection against kidney toxicity has been achieved by vigorous parenteral hydration and forced diuresis. Even with this strategy however severe nephrotoxicity develops for doses higher than 100-l 20 mg/m’. Following the experimental data of Litterst (5), 0~01s (7) was able, by administering cisplatin in hypertonic (3%) saline and maintaining extensive hydration, to reach 200 mg/m’ per cycle without important nephrotoxicity. With this high dosage the dose-limiting toxicity was a very severe peripheral neuropathy and ototoxicity. Many pharmacological attempts to decrease cisplatin toxicity have been made utilizing a number of thiol compounds as potential chemoprotectors (see Table 2). One of the best studied is diethyldithiocarbamate (DDTC) which seems able to remove platinum from mono-guanine adducts, but is completely unreactive toward the cisplatinhis-guanine adducts (1). It seems possible that due to these reactions DDTC has the unique ability to ‘rescue’ normal tissues from platinum toxicity even ifadministered after cisplatin treatment. Unfortunately, DDTC does not protect the bone marrow and has severe acute side-effects that make its clinical use very difficult. The major side-effects are severe Table
2.
Methods toxicity turnour
and of drugs
agents to reduce platinum anti-
Hydration Hypertonic saline + hydration Diethyldithiocarbamate (DDTC) Thiosulfate WR-272 1 ORG.2766 Glutathione
PLATINUM-INDUCED
diaphoresis,
profound
uneasiness
and anxiety,
TOXICITY
REDUCTION
chest discomfort,
141
hypertension
and flushing
(9). Thiosulfate is another thiol compound that has been shown experimentally to be able to reduce cisplatin-induced nephrotoxicity but only when administered prior to cisplatin. It is ineffective on other systemic toxicities. Moreover, thiosulfate can interfere with the antitumour activity ofcisplatin. For this reason it has been proposed for the so-called ‘tworoute chemotherapy’ that is for loco-regional treatment (e.g. intraperitoneal cisplatin) with systemic protection (4). WR-2721 is an aminothiol, used as a radioprotector which also shows interesting selective protection against the toxicity of alkylating agents and cisplatin. The basis for the selectivity of WR-2721 is not well understood but it seems likely to be due to its hydrolysis to the free thiol (WR-1065) which is selectively taken up by normal cells in comparison with cancer cells. It is effective only when administered just prior to cisplatin. Its major side-eflect is hypotension (especially with high doses; 910 mg/m’) but nausea, vomiting, flushing and somnolence have also been reported. The preliminary clinical results of the combination of cisplatin (up to 150 mg/m’) with WR-2721 are promising, even though some neuro- and ototoxicities have been observed (3). Caution is however required since WR-272 1 is a potent inactivator of y-glutamylcysteine synthetase, thus reducing hepatic glutathione, which could result in an increase of the toxicity of a variety of free radical generating agents ( 10). ORG.2766, an ACTH, 9 analog devoid of the hormonal effect of ACTH, is a neurotrophic peptide that is able to experimentally protect animals from the neurotoxicity of cisplatin. The mechanism of action is not clear but it seems not to be related to an interference with the cisplatin-DNA binding in dorsal root spinal ganglia (11). The preliminary clinical results are encouraging. One compound which has been extensively studied and whose modulation has been shown to alter the cell response to a variety of anticancer agents, is glutathione (GSH). A variety of approaches have been tried with the object of manipulating the GSH level within tumour cells in order to increase their susceptibility to antitumour agents or to increase the protection of normal cells. Buthionine sulfoximine, for example, a potent inhibitor of y-glutamylcysteine synthetase, has been used to decrease the cellular level of GSH, especially for resistant tumour cells whose resistance could be linked to an increase of GSH (6). The results so far achieved are inconsistent, with the toxicity sometimes being increased more than the cell susceptibility. Another approach has been to administer high-dose GSH intravenously with the aim of ‘activating’ the y-glutamyl cycle to gain better protection of cells rich in transpeptidase (kidney, bladder) and to simultaneously increase the efficacy of anticancer compounds through the activation of transport mechanisms. The uptake of extracellular GSH by most tissues (and by cancer cells) is undetectable or very low and a direct reaction of GSH with drugs such as cisplatin in plasma is very unlikely. The results of experimental studies, however, showed not only a good protection against the toxicity of cisplatin, cyclophosphamide and ifosfamide, but also some improvement of antitumour activity of cisplatin ( 12, 13). Since the first clinical trials confirmed the good protection against cisplatin and cyclophosphamide-induced toxicities, a trial in patients with advanced bulky ovarian cancer treated with five cycles (one every 3-4 weeks) of GSH (1500 mg/m’ i.v., 15 min before cisplatin) plus high-dose cisplatin (40 mg/m’ x 4 days) plus cyclophosphamide (600 mg/m* on day 4) and with ‘normal’ hydration (2000 ml of saline per day) was performed at the Instituto Nazionale Tumori in Milan. ‘I’he first results of this pivotal trial were
142
S. TOGNELLA
recently communicated (2) and are very impressive. No nephrotoxicity was seen, even with such moderate hydration, myelosuppression was mild and neurotoxicity, never associated with motor dysfunction, was a frequent but not severe (grade l-2) and reversible cumulative side-effect after four to five cycles. Fifty-one patients so far are evaluable. The overall response rate is 82%, with 59% complete responses. Even in the group of patients with a tumour size larger than 5 cm after the surgical operation a complete response was seen in 44%. The excellent protection against the toxicities (including neurotoxicity) of cisplatin in high-dose regimens, and the lack of any intrinsic toxicity of glutathione make the latter a good candidate for clinical trials which seek to test the possibility of increasing the therapeutic index of cisplatin.
References 1. Bodenner,
D. L., Dedon,
P. C., Keng,
P. C. & Borch,
diamminedichloroplatinum (II)-induced inhibition. Cancer Res. 46: 2745-2750. 2. Bohm, S., di Re, F., Oriana, S., Spatti, High dose cisplatin with glutathione Meeting 3. Glover,
International D., Grabelsky,
Gynecological S., Fox, K.,
cytotoxicity,
R. F. (1986) DNA
Effect
cross-linking,
ofdiethyldithiocarbamate
on cZS-
and y-glutamyl-transpeptidase
G. B., Tedeschi, M., Tognella, S., Veronesi, P. & Zunino, F. (1989) protection in patients with bulky advanced ovarian cancer. 2nd
Cancer Society, Toronto, 1989 (abstract). Weiler, C., Cannon, L. & Glick, J. (1989)
Clinical
trials
of WR-2721
and &platinum. Znt. J. Radial. Oncol. Biol. Phys. 16: 1202-1204. 4. Kobayashi, H., Hasuda, K., Aoki, K., Kuroiwa, T., Taniguchi, S. & Baba, T. (1989) “Two-route chemotherapy” using cis-diamminedichloroplatinum (II) and its antidote, sodium thiosulfate, combined with angiotensin II is effective against peritoneally 141-147. 5. Litterst, C. L. (1981) Alterations in the toxicity of platinum as a function of NaCl concentration
disseminated
cancer
in rats.
Cancer Chemother.
of&-dichlorodiammineplatinum in the vehicle of administration.
Pharmacol.
24:
II and in tissue localization
Toxicol.
Appl. Pharmacol.
61: 99-108. 6. Mitchell, J. B. (1988) Glutathione modulation and cancer treatment. ISI Atlas Sci. Pharmacol. 2: 155-160. 7. Ozols, R. F., Corden, B. J., Jacob, J., Wesley, M. N., Ostchega, Y. & Young, R. C. (1984) High-dose cisplatin in ovarian cancer. Ann. Int. Med. 100: 19-24. 8. Rosenberg,
Inhibition
of cell division
products from a platinum electrode. Nature 205: 6988699. 9. Rothenberg, M. L., Ostchega, Y., Steinberg, S. M., Young, dose carboplatin with diethyldithiocarbamate chemoprotection
B., van
Camp,
L. & Krigas,
T. (1965)
R. C., Hummel, in treatment
in Escherichia
coli by electrolysis
S. & Ozols, R. F. (1988) Highofwomen with relapsed ovarian
cancer. J. N&l. Cancer Inst. 80: 1488-1492. 10. Shor, N. F. (1988) Mechanism of synergistic toxicity of the radioprotective agent WR-2721, and 6hydroxydopamine. Biochen. Pharmacol. 37: 1751-1762. 11. Terheggen, P. M. A. B., van der Hoop, R. G., Float, B. G. J. & G’ 1sp en, W. H. (1989) Cellular distribution of cis-diamminedichloroplatinum(II)-DNA b’m d’ m g in rat dorsal root spinal ganglia: effect of the neuroprotecting peptide ORG.2766. Toxicol. Appl. Pharmacol. 99: 334-343. 12. Zunino, F., Pratesi, G., Micheloni, A., Cavalletti, E., Sala, F. & Tofanetti, 0. (1989) reduced glutathione against cisplatin-induced renal and systemic toxicity and its influence activity 13. Zunino, against 111.
of the antitumor drug. Chem. Biol. Interact. 70: 899101. F., Tofanetti, O., Besati, A., Cavalletti, E. & Savi, G. (1983) cis-dichlorodiammine platinum (II)-induced nephrotoxicity
Protective effect of on the therapeutic
Protective effect ofreduced glutathione and lethal toxicity. Tumori 69: 1055
