Search

cis-Dichlorodiammineplatinum(II) has shown good broad-spectrum activity in the current Division of Cancer Treatment (National Cancer Institute) tumor panel. It meets Decision Network criteria for activity in at least five of ten tumor systems (the ip B16 melanoma, the sc CD8F1 mammary carcinoma, the ip colon tumor 26, the ip L1210 leukemia, and the ip P388 leukemia). Activity against the sc colon tumor 38, the iv Lewis lung tumor, the ic ependymoblastoma, and the human breast tumor xenograft (MX-1) was marginal. No activity was detected against the human lung tumor xenograft (LX-1), but good, reproducible activity was observed against the murine M5076 ovarian carcinoma. No schedule-dependency was observed after ip administration against the ip L1210 leukemia. The recently developed subrenal capsule assay offers promise as a rapid way (less than or equal to 11 days) of ranking the sensitivity of a variety of human tumors to cis-dichlorodiammineplatinum(II) and other chemotherapeutic agents.

The synthesis, physical properties, and antitumor activity of the cis-, d,l-trans-, d-trans-, and l-trans- stereoisomers of 1,2-diaminocyclohexane tetrachloroplatinum(IV) are described. The objective of the study was to produce a platinum complex with activity against cisplatin-resistant tumor cells and with suitable pharmaceutical properties for formulation development. The isomers had the following solubilities in saline: cis-, 2 mg/ml; d,l-trans-, 6.5 mg/ml; and d-trans- and l-trans-, 15-16 mg/ml. The four complexes showed slightly better activity than cisplatin against the ip implanted murine L1210 leukemia. In contrast to cisplatin, all complexes produced significant increases in life span against L1210/cisplatin, a subline of L1210 with acquired resistance to cisplatin. However, the cis- isomer was less active against L1210/cisplatin. The d,l-trans- isomer (tetraplatin) was selected for further studies based on greater ease for large-scale synthesis. It showed superior activity to cisplatin against P388/cisplatin and like cisplatin showed significant and reproducible activity against the ip implanted B16 melanoma, ip implanted M5076 sarcoma, ip implanted P388 leukemia, and MX-1 human breast xenograft implanted under the renal capsule. Purity and stability (greater than 24 hours in saline) were evaluated by high-performance liquid chromatography and found to be suitable for development of a parenteral dosage form. Preliminary studies in a rat model (to be reported elsewhere) showed it to be less nephrotoxic than cisplatin on a molar basis and worthy of further study.