nk-121 and Leukopenia

CDDP is an extremely active antineoplastic agent, yet has severe renal, upper GI and neurotoxicity. Therefore, extremely careful supportive care is necessary to administer this agent to patients. There are two ways to improve this agent. The first is to improve the activities of this agent, including widening the spectrum. The other is to reduce toxicity. By these two ways, the therapeutic window or efficacy of the agents will be increased. In these two factors in mind, 4 analogues, CBDCA, 254S, DWA 2114R and NK-121 are in clinical trials in Japan. These 4 agents are different from mother compound CDDP, that is the DLF is bone marrow depression with rather mild renal and upper GI toxicities with different degrees among analogues, compared with those of CDDP. Therefore, these 4 agents do not need hydration before and after the administration. The extensive studies of pharmacokinetics and dynamics are studied including plasma levels, protein bindings and urinary excretions. These above studies indicate some correlations in efficacy and toxicity, but not perfectly correlated. The experiences of the above 4 analogues are still too short to predict the possibility of neurotoxicity, however, it seems to be 4 analogues also neurotoxic. Above findings strongly suggests that the more clinical experiences are necessary to evaluate these analogues.

Topics: Antineoplastic Agents; Carboplatin; Chemical Phenomena; Chemistry; Cisplatin; Female; Humans; Kidney; Leukopenia; Nervous System; Organoplatinum Compounds; Platinum; Protein Binding; Thrombocytopenia

Since the introduction of Cisplatin (CDDP) into clinical practice in 1972, CDDP has assumed an important role in the treatment of various tumors. But its renal toxicity has been proved to be a dose limiting factor. Thus the total number of courses which may be given is limited. For this reason, efforts have been made to develop CDDP analogues with reduced toxicities, especially renal toxicity, and more enhanced antitumor activity, and they are now reaching the clinical testing phase. Among them Carboplatin (CBDCA), 254-S, DWA 2114R and NK 121 have been well studied. These analogues were noted to be less nephrotoxic, but more myelosuppressive than CDDP in preclinical analysis. As for cytotoxicity, their inhibitory effects on tumor growth in murine experimental system were similar or more to that of CDDP. Due to these data clinical trials have been carried out. Phase I studies have shown that these analogues are relatively free of renal toxicity as evaluated in preclinical studies and that their dose limiting factor is myelosuppression. Estimation of cross resistance to CDDP and antitumor spectrum have been studied at phase II trials which are ongoing. Interim reports have not shown that enhanced tumor activity or enlarged antitumor spectrum are expected.

Topics: Animals; Antineoplastic Agents; Bone Marrow; Carboplatin; Cisplatin; Drug Evaluation; Drug Screening Assays, Antitumor; Humans; Kidney; Leukopenia; Mice; Neoplasms; Neoplasms, Experimental; Organoplatinum Compounds; Thrombocytopenia