Pharmacological and preclinical toxicological studies of 1,2-diaminocyclohexane(isocitrato)platinum(II).
The antitumor activity of a new highly water-soluble platinum derivative, (1,2-diaminocyclohexane)(isocitrato)platinum(II) (NSC 350602; PHIC), was studied in L1210 leukemia cells inoculated into mice. PHIC was found to be active for i.p. graft-i.p. treatment, i.p. graft-i.v. treatment, and i.v. graft-p.o. treatment. A significant activity was observed on early and advanced L1210 leukemia even when the treatment was delayed 6 days after the graft. A comparison between the activities of PHIC, cisplatin (NSC 119875), and (4-carboxyphthalato)(1,2-diaminocyclohexane)-platinum(II) (NSC 271674; DACCP) for i.p. graft-i.p. treatment indicated that the highest activity was observed for divided doses rather than single dose in the case of PHIC and DACCP and not for cisplatin. Under these conditions, PHIC gave larger treated versus control survival time values or a greater number of surviving animals than did cisplatin and DACCP. No cross-resistance between PHIC and cisplatin could be detected in L1210 leukemia cells resistant to cisplatin. Mutagenicity studies on Salmonella typhimurium revealed that PHIC is far less mutagenic than cisplatin on TA100 and TA98 strains. Other pharmacological parameters, such as growth inhibition rate of cultured L1210 cells, penetration, and DNA binding in L1210 cells inoculated in mice, were compared for PHIC and cisplatin together with their in vitro rates of hydrolysis and platinum:DNA adducts. No nephrotoxicity was detected with PHIC at the maximum nonlethal dose level in mice in contrast to results with cisplatin. A preclinical study was conducted in baboons at 100, 150, and 200 mg/kg. No nephrotoxicity could be detected at a dose of 100 mg/kg without prehydration for six courses at 3-week intervals. At 200 mg/kg, an increase of blood creatinine was controlled by prehydration. Gastrointestinal toxicity was mild during the three regimens. Phase I clinical trials are under way.
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity; D004273:DNA, Neoplasm / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance; D007939:Leukemia L1210 / Q000188:drug therapy*; D051379:Mice; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D009152:Mutagenicity Tests; D009153:Mutagens
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009153:Mutagens; D002945:Cisplatin