This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by DeConti, R. C. Articles by Creasey, W. A. Search for Related Content PubMed PubMed Citation Articles by DeConti, R. C. Articles by Creasey, W. A.

Clinical and Pharmacological Studies with cis-Diamminedichloroplatinum(II)¹

Sections of Oncology and Cancer Chemotherapy [R. C. D., B. R. T., W. A. C.] and Nuclear Medicine [R. C. L.] Yale University School of Medicine, New Haven, Connecticut 06510

cis-Diamminedichloroplatinum(II) is the first of a group of platinum coordination complexes with antineoplastic activity to be studied in humans. This Phase I investigation characterizes the toxicity and pharmacological disposition of the drug in 10 patients. Plasma levels of cis-diamminedichloroplatinum(II) decayed in a biphasic mode, with an initial half-life of 25 to 49 min and a secondary phase ranging from 58 to 73 hr. Protein binding exceeded 90% of radioactivity in this phase. Intracellular leukocyte levels approximated 6 to 11% of coincident plasma samples. Urinary excretion was incomplete, with only 27 to 45% of radioactivity excreted in the first 5 days. The initial fractions of radioactivity were largely unchanged drug, although this changed with time. The incorporation of thymidine-³H into DNA was inhibited in leukemic leukocytes only after prolonged exposure in vitro to cis-diamminedichloroplatinum(II). Acute lymphocytic cells appeared more sensitive than myelocytic cells in vitro, although the only objective antineoplastic response noted was a transient decrease in blast count in a patient with acute myelocytic leukemia. Renal impairment was the dose-limiting toxicity in the single-dose escalation scheme used. Rises in serum creatinine occurred in three of six patients who received doses of 1.95 mg or more per kg, and progressive renal failure contributed to the death of one patient.

¹ Supported in part by Grants CA 5138, Ca 08341, and Ca 12317 from the USPHS, as well as by Grant ET-14G from the American Cancer Society.

Received 9/28/72. Accepted 3/14/73.

This article has been cited by other articles:

				M. H. Hanigan, M. Deng, L. Zhang, P. T. Taylor Jr., and M. G. Lapus Stress response inhibits the nephrotoxicity of cisplatin Am J Physiol Renal Physiol, January 1, 2005; 288(1): F125 - F132. [Abstract] [Full Text] [PDF]

				J. M. Rademaker-Lakhai, C. Terret, S. B. Howell, C. M. Baud, R. F. de Boer, D. Pluim, J. H. Beijnen, J. H. M. Schellens, and J.-P. Droz A Phase I and Pharmacological Study of the Platinum Polymer AP5280 Given as an Intravenous Infusion Once Every 3 Weeks in Patients with Solid Tumors Clin. Cancer Res., May 15, 2004; 10(10): 3386 - 3395. [Abstract] [Full Text] [PDF]

				D. M. Townsend, M. Deng, L. Zhang, M. G. Lapus, and M. H. Hanigan Metabolism of Cisplatin to a Nephrotoxin in Proximal Tubule Cells J. Am. Soc. Nephrol., January 1, 2003; 14(1): 1 - 10. [Abstract] [Full Text] [PDF]

				M. H. Hanigan, E. D. Lykissa, D. M. Townsend, C.-N. Ou, R. Barrios, and M. W. Lieberman {gamma}-Glutamyl Transpeptidase-Deficient Mice Are Resistant to the Nephrotoxic Effects of Cisplatin Am. J. Pathol., November 1, 2001; 159(5): 1889 - 1894. [Abstract] [Full Text] [PDF]

				K. Hanada, K. Nishijima, H. Ogata, S. Atagi, and M. Kawahara Population Pharmacokinetic Analysis of Cisplatin and Its Metabolites in Cancer Patients: Possible Misinterpretation of Covariates for Pharmacokinetic Parameters Calculated from the Concentrations of Unchanged Cisplatin, Ultrafiltered Platinum and Total Platinum Jpn. J. Clin. Oncol., May 1, 2001; 31(5): 179 - 184. [Abstract] [Full Text] [PDF]

				F. Kanzawa, F. Koizumi, Y. Koh, T. Nakamura, Y. Tatsumi, H. Fukumoto, N. Saijo, T. Yoshioka, and K. Nishio In Vitro Synergistic Interactions between the Cisplatin Analogue Nedaplatin and the DNA Topoisomerase I Inhibitor Irinotecan and the Mechanism of this Interaction Clin. Cancer Res., January 1, 2001; 7(1): 202 - 209. [Abstract] [Full Text]

				D. L. Clark, P. A. Andrews, D. D. Smith, J. J. DeGeorge, R. L. Justice, and J. G. Beitz Predictive Value of Preclinical Toxicology Studies for Platinum Anticancer Drugs Clin. Cancer Res., May 1, 1999; 5(5): 1161 - 1167. [Abstract] [Full Text] [PDF]

				N. Nagai, H. Ogata, Y. Wada, D. Tsujino, K. Someya, T. Ohno, K. Masuhara, Y. Tanaka, H. Takahashi, H. Nagai, et al. Population Pharmacokinetics and Pharmacodynamics of Cisplatin in Patients with Cancer: Analysis with the NONMEM Program J. Clin. Pharmacol., November 1, 1998; 38(11): 1025 - 1034. [Abstract] [PDF]

				A. I. Ivanov, J. Christodoulou, J. A. Parkinson, K. J. Barnham, A. Tucker, J. Woodrow, and P. J. Sadler Cisplatin Binding Sites on Human Albumin J. Biol. Chem., June 12, 1998; 273(24): 14721 - 14730. [Abstract] [Full Text] [PDF]

				P. S. Turk, J. F. Belliveau, J. W. Darnowski, M. C. Weinberg, L. Leenen, and H. J. Wanebo Isolated Pelvic Perfusion for Unresectable Cancer Using a Balloon Occlusion Technique Arch Surg, May 1, 1993; 128(5): 533 - 539. [Abstract] [PDF]

				A. Wile and M. Smolin Hyperthermic Pelvic Isolation-Perfusion in the Treatment of Refractory Pelvic Cancer Arch Surg, November 1, 1987; 122(11): 1321 - 1325. [Abstract] [PDF]

				H. Tanaka, E. Ishikawa, S. Teshima, and E. Shimizu Histopathological Study of Human Cisplatin Nephropathy Toxicol Pathol, February 1, 1986; 14(2): 247 - 257. [Abstract] [PDF]

				J. D. BLACHLEY and J. B. HILL Renal and Electrolyte Disturbances Associated with Cisplatin Ann Intern Med, November 1, 1981; 95(5): 628 - 632. [Abstract] [PDF]

				W. M. BENNETT, R. S. MUTHER, R. A. PARKER, P. FEIG, G. MORRISON, T. A. GOLPER, and I. SINGER Drug Therapy in Renal Failure: Dosing Guidelines for Adults: Part II: Sedatives, Hypnotics, and Tranquilizers; Cardiovascular, Antihypertensive, and Diuretic Agents; Miscellaneous Agents Ann Intern Med, August 1, 1980; 93(2): 286 - 325. [Abstract] [PDF]

				M. ROZENCWEIG, D. D. VON HOFF, M. SLAVIK, and F. M. MUGGIA Cis-diamminedichloroplatinum (II) A New Anticancer Drug Ann Intern Med, June 1, 1977; 86(6): 803 - 812. [Abstract] [PDF]