Cisplatin (cis-diamminedichloroplatinum II).

Summary Preclinical 1.Cisplatin is a co-ordination complex of a central platinum atom, two chlordies and two ammonia molecules in the "cis" position. 2.A prime mechanism of inhibition of tumor growth by cisplatin appears to be inhibition of DNA synthesis. 3.Cisplatin produces intrastrand and interstrand crosslinks in DNA. 4.The plasma t 1/2 α of cisplatin (as determined by platinum measurements) was 30–60 min. The t 1/2 β was 2–3 days. 5.Urinary excretion accounted for 60–70% and 27–45% of the administered dose of cisplatin in animals and humans respectively. 6.Cisplatin was rapidly bound to plasma proteins after i.v. administration with a plasma t 1/2 β of the "free durg" of 32–53 min. 7.The principal dose limiting toxicity of cisplatin in animals was renal toxicity. 8.Other major toxicities of cisplatin in animals included myelosuppression, gastro-intestinal, hepatic and ototoxicity. Clinical (a) Efficacy Cisplatin has demonstrated antitumor activity as a single agent and in combination with other antitumor drugs in the following metastatic tumors. o 1.Testicular cancer—An active drug combination included cisplatin (20 mg/m 2 daily × 5 or 120 mg/m 2 single dose), bleomycin, vinblastine with the addition of cyclo-phosphamide and actinomycin D in some regimens. Complete response rates of 60–70% have been reported and the survival times of these patients have been significantly increased over patients receiving other therapy. 2.Ovarian cancer—Cisplatin has shown activity in ovarian cancer as single agent (50–100 mg/m 2 ) and in combination with adriamycin. Survival times of complete responders have been significantly increased over those obtained with standard alkylating agent therapy. 3.Other adult tumors—Cisplatin has demonstrated activity as a single agent and in combination chemotherapy in metastatic tumors of the urinary bladder, cervix, head and neck, and prostate. 4.Pediatric tumors—Antitumor activity of cisplatin has been observed in pediatric patients with osteogenic sarcoma and neuroblastoma. (b) Toxicity o 1.Renal toxicity—Dose related and cumulative renal insufficiency was the major dose-limiting toxicity of cisplatin. It was first noted during the second week after a dose of cisplatin. 2.Hematologic—Cisplatin-induced myelosuppression was dose related and occurred in approximately 25–30% of patients treated. The nadirs in circulating platelets and leukocytes occurred between days 18–23 after a dose of cisplatin. 3.Ototoxicity—Dose related and cumulative ototoxicity has been associated with cisplatin therapy. This toxicity was manifested by loss of hearing in the high frequency range (4000–8000 Hz). 4.Nausea and Vomiting—Nearly all patients treated with cisplatin have experienced nausea and vomiting. In most cases antiemetics have been ineffective in controlling emesis. 5.Other toxicities—Ncurotoxicity, characterized by peripheral neuropathies, hyperuricemia and anaphylactic-like reactions have been reported to occur infrequently after cisplatin administration. Neurotoxicity appeared to be total dose related. (c) Mode of administration Three modes of cisplatin administration have significantly reduced the incidence and severity of renal toxicity. o 1.Patients received intravenous hydration with 1 to 21 of saline for 8 to 12 h prior to a 15 min intravenous infusion of cisplatin in saline and followed by saline hydration for 24 h. 2.Patients received intravenous hydration with 21 of 5% glucose in 0.5 n-saline, and 12.5 g mannitol immediately prior to a 10–15 min infusion of cisplatin followed by a continuous infusion of 10 g/h mannitol in 0.5 n-saline over the next 6 h. 3.Patients received cisplatin mixed with 37.5 g mannitol and 40 mg furosemide administered as an intravenous infusion with 2 1 of 5% dextrose in 0.33 n-saline for 6 to 8 h. Patients received subsequent hydration to replace fluids lost as a result of emesis and diuresis.