Oxalatoplatinum (I-OHP): Experimental and Clinical Studies

Abstract

1,2 diamino cychlohexane (trans-I) oxalatoplatinum II was isolated by Kidani among isomeric mixture of DACH derivatives of Platinum as yielding the highest survival increment on L1210 leukemia.

It is more active than CDDP on L1210 leukemia and is active on L1210 and murine lymphoma grafted intra cerebrally. It is also active on AKR leukemia, P 388, MA 16-C, B 16 melanoma, lewis lung, colon C 26, fibrosarcoma M 5076. Its toxicity profile on experimental animals is different from that of CDDP and CBDCA since it is totally devoid of renal toxicity on classical and enzymuria studies (Cambar) and almost totally devoid of hematologic toxicity. It can be combined with CBDCA at full doses of both drugs simultaneously without enhancement of lethal toxicity and a major increase of cure rate of L1210. Combination with 5-FU results in a significant potentiation on L1210 leukemia. Time-dependant toxicity studies showed major differences in lethal, digestive and hematologic toxicities according to time of administration.

Human studies: Phase I studies confirmed the total absence of renal toxicity and almost total absence of hematologic toxicity except in heavily pretreated patients. Gastro intestinal toxicity persists but is manageable with modern anti emetic drugs. Recommended dose for phase II studies is 100–130mg/m² q 3 w but toxicity can be lessened by chronomodulation: if given in the evening the dose can be raised to 200–220mg/m². I-OHP exhibits a special type of neurotoxicity dominated by short term (3–4 days) non cumulative acroparesthesias which very rarely imply drug discontinuation.

Significant antitumor activity has already been observed in single drug ongoing phase II trials in melanoma (30%), ovarian carcinoma (25%), glioma (2/7), non hodgkin’s lymphoma (3/8) and colon carcinoma (2/14). Urothelial tumors are under investigation as well as breast, head and neck, lung tumors.

Combined with 5-FU and folinic acid in a chronomodulated design with programmable pumps a 66% (57/86) response rate has been observed in advanced colo rectal carcinoma.