The effect of diethyldithiocarbamate on the haematological toxicity and antitumour activity of carboplatin.
Carboplatin has recently been established as an effective agent in cancer chemotherapy. The dose limiting toxicity of this platinum complex is myelosuppression and, in this study, we have shown that through the use of diethyldithiocarbamate (DDTC), a protective thiol compound, the toxicity in rodents can be ameliorated and lethality prevented. DDTC protected against carboplatin-induced leucopoenia and anaemia when administered as a single bolus or as a multiple schedule incorporating three injections. With the single bolus, the effectiveness of this protection decreased as the lag time between carboplatin and DDTC administrations increased. Thrombocytopoenia was unaffected by DDTC. The growth profile of ADJ/PC6A tumour in mice was dependent on the timing of DDTC administration when given in combination with the platinum complex. The tumour growth delay, however, was unaffected by DDTC at any schedule. Multiple injections of DDTC increased the ED90 for carboplatin from 5.0 to 7.5 mg/kg. The LD50 value was increased from 115 to 216 mg/kg with the same DDTC schedule. Thus, DDTC improved the therapeutic index of carboplatin by 25%. A clinical role for the use of DDTC as a protective agent for carboplatin-induced toxicities is suggested.
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Drug Development Section, Institute of Cancer Research, Sutton, Surrey, U.K.
Siddik
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Boxall
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Harrap
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D000740:Anemia / Q000517:prevention & control; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects*; D016190:Carboplatin; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use; D004050:Ditiocarb / Q000627:therapeutic use*; D005260:Female; D006400:Hematocrit; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000009:adverse effects* / Q000627:therapeutic use; D051381:Rats
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D004050:Ditiocarb; D016190:Carboplatin; D002945:Cisplatin