Summary
(R)-(-)-1,1-(2-amino-methylpyrrorodine)-platinum(II) (DWA2114R), cis-1,1-cyclobutanedicarboxylato(2R)-2-methyl-1,4-butanediammineplatinum(II) (NK121; CI-973) and glycolate-o,-o′-diammine platinum(II) (254-S; NSC375101D) are new platinum compounds developed in Japan. We studied the antitumor effects of these compounds on the cisplatin (cis-diamminedichloroplatinum, DDP)-resistant human leukemia cell line, K562/DDP. K562/DDP cells were 10-fold resistant to DDP, while the cells showed minimal cross-resistance to carboplatin (2.1-fold) and DWA2114R (3.3-fold), and were as sensitive to NK121 (1.6-fold) and 254-S (1.0-fold) as the parent cells. Increases in exposure time of K562 cells to DWA2114R resulted in progressive shifting of the dose-response curve to the left, or more effective cell growth inhibition of the cells. Time dependency indices (ID80 obtained from dose-response curve after 1 hr-exposure of K562 cells to drug followed by 72 hr-culture without drug/ID80 after 24 hr-exposure) of DDP, NK121 and 254-S were 10, 8 and 20, respectively. A multidrug resistant cell-line, MOLT-3/TMQ200, was as sensitive to platinum compounds as the parent MOLT-3 cells. Little or no influence of tumor cell density was observed in the growth inhibition of MOLT-3 or K562 cells induced by these new compounds even if cells were concentrated to a density of 108 cells/ml. These results indicate that NK121 and 254-S may overcome the drug resistance developed in the patients after treatment with DDP. The antitumor effect of DWA2114R is more dependent not only on drug-concentration but also on exposure time than that of DDP, suggesting that continuous infusion rather than bolus administration appears the favorable schedule in clinical trials.
Similar content being viewed by others
References
Prestayko AW, D'Aoust JC, Issel BF, Crooke ST: Cisplatin (cis-diamminedichloroplatinum II). Cancer Treatment Rev 6:17–39, 1979
Ohnuma T, Arkin H, Holland JF: Effects of cell density on drug-induced cell kill kinetics in vitro (inoculum effect). Br J Cancer 54:415–421, 1986
Velasquez W, Cabanillas F, Salvador P, McLaughlin P, Fridrik M, Tucker S, Jagannath S, Hagemeister FB, Redman JR, Swan F, Barlogie B: Effective salvage therapy for lymphoma with cisplatin in combination with high dose Ara-C and dexamethasone (DHAP). Blood 71:117–122, 1988
Talley RW, O'Bryan RM, Gutterman JU, Brownlee RW, McCredie B: Clinical evaluation of toxic effects of cis-diamminedichloroplatinum (NSC-119875)-phase I clinical study. Cancer Chemother Rep 57:465–471, 1973
Majima H: Present status of cisplatin analogues in Japan, Jpn J Cancer Chemother 16:1373–1377, 1989
Tamura K, Makino S, Araki Y: Phase I trial of DWA2114R, a new cisplatinum compound, for hematological malignancies (Abstract). Proc Am Soc Clin Oncol 9:208, 1990
Theriault R, Esparza L, Raber M, Newman R, Krakoff I, Cohen I, Kowal C: Phase I evaluation of [SP-4–3(R)]-[1,1-cyclobutanedicarboxylato(2-)] (2-methyl-1,4-butanediamine-N,N′) platinum (CI-973) (Abstract). Proc Am Assoc Cancer Res 31:197, 1990
Sasaki Y, Amano T, Morita M, Shinkai T, Eguchi K, Tamura T, Ohe Y, Kojima A, Saijo N: Phase I study of pharmacological analysis of cis-diammine(glycolato)platinum (254-S; NSC375101D) administered by 5-day continuous intravenous infusion. Cancer Res 51:1472–1477, 1991
Takemura Y, Kobayashi H, Miyachi H, Hayashi K, Sekiguchi S, Ohnuma T: The influence of tumor cell density on cellular accumulation of doxorubicin or cisplatin in vitro. Cancer Chemother Pharmacol 27:417–422, 1991
LeRoy AF, Wehling ML, Sponseller HL, Friauf WS, Solomon RE, Dedrick RL: Analysis of platinum in biological materials by flameless atomic absorption spectrophotometry. Biochemical Med 18:184–191, 1977
Lozzio CB, Lozzio BB: Human chronic myelogenous leukemia cell line with positive Philadelphia chromosome. Blood 45:321–334, 1975
Minowada J, Ohnuma T, Moore GE: Rosette-forming human lymphoid cell lines. I. Establishment and evidence for origin of thymus-derived lymphocyte. J Natl Cancer Inst 49:891–895, 1972
Scanlon KJ, Kashani-Sabet M, Miyachi H: Differential gene expression in human cancer cells resistant to cisplatin. Cancer Invest 7:581–587, 1989
Takemura Y, Ohnuma T, Chou TC, Okano T, Holland JF: Biologic and pharmacologic effects of harringtonine on human leukemia-lymphoma cells. Cancer Chemother Pharmacol 14:206–210, 1985
Arkin H, Ohnuma T, Kamen BA, Holland JF, Vallabhajosula S: Multidrug resistance in a human leukemia cell line selected for resistance to trimetrexate. Cancer Res 49:6556–6561, 1989
Miyachi H, Takemura Y, Kobayashi H, Ohnuma T: CB3717 induced enhancement of multidrug resistance in a trimetrexate-resistant human acute lymphoblastic leukemia cell line (Abstract). Proc Am Assoc Cancer Res 31:380, 1990
Salem P, Hall SW, Benjamin RS, Murphy WK, Wharton JT, Bodey GP: Clinical phase I–II study of cis-dichlorodiammineplatinum(II) given by continuous iv infusion. Cancer Treat Rep 62:1553–1555, 1978
Takahashi K, Seki T, Nishikawa K, Minamide S, Iwabuchi M, Ono M, Nagamine S, Horinishi H: Antitumor activity and toxicity of serum protein-bound platinum formed from cisplatin. Jpn J Cancer Res 76:68–74, 1985
Okamoto M, Takao A, Fujita H: Pharmacokinetics of cisplatin and new cisplatin analogues in experimental animals. Chemotherapy 38:639–645, 1990
Sasaki Y, Tamura T, Eguchi K, Shinkai T, Fujiwara Y, Fukuda M, Ohe Y, Bungo M, Horichi N, Niimi S, Minato K, Nakagawa K, Saijo N: Pharmacokinetics of (glycolato-0,0′)-diammine platinum(II), a new platinum derivative, in comparison with cisplatin and carboplatin. Cancer Chemother Pharmacol 23:243–246, 1989
Author information
Authors and Affiliations
Additional information
Address for offprints: Y. Takemura, Department of Laboratory Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359, Japan
Rights and permissions
About this article
Cite this article
Kobayashi, H., Takemura, Y., Miyachi, H. et al. Antitumor activities of new platinum compounds, DWA2114R, NK121 and 254-S, against human leukemia cells sensitive or resistant to cisplatin. Invest New Drugs 9, 313–319 (1991). https://doi.org/10.1007/BF00183571
Issue Date:
DOI: https://doi.org/10.1007/BF00183571