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 Kelland, L. R. Articles by Harrap, K. R. Search for Related Content PubMed PubMed Citation Articles by Kelland, L. R. Articles by Harrap, K. R.

Preclinical Antitumor Evaluation of Bis-acetato-ammine-dichloro-cyclohexylamine Platinum(IV): an Orally Active Platinum Drug¹

Drug Development Section, The Institute of Cancer Research, Belmont, Sutton, Surrey SM2 5NG, United Kingdom [L. R. K., G. A., M. J. M., M. J., P. M. G., M. V., K. R. H.]; and Johnson Matthey Technology Center, Sonning, Reading, United Kingdom [B. A. M.]

The cytotoxicity of a novel platinum(IV) complex, bis-acetato-ammine-dichloro-cyclohexylamine platinum(IV) (JM216), has been evaluated in vitro against a panel of human tumor cell lines (predominantly ovarian) representative of models of intrinsic and acquired resistance to cisplatin. In addition, the activity of JM216 administered by the p.o. route has been determined in vivo using the murine ADJ/PC6 plasmacytoma and four human ovarian carcinoma xenograft lines. In vitro, against seven human ovarian carcinoma cell lines, JM216 showed similar cytotoxicity and pattern of cytotoxicity to cisplatin (mean 50% inhibitory concentrations of 3.5 µM for cisplatin and 1.7 µM for JM216). The cytotoxicity of JM216 was more dependent on the time of drug exposure than that of cisplatin, suggesting that extended split-dosing rather than a single bolus administration might be a more appropriate schedule in patients. Using six pairs of acquired cisplatin-resistant and parent human tumor cell lines (four ovarian, one testicular, and one cervical) JM216 exhibited non-cross-resistance (resistance factor of <1.5) in three whereas tetraplatin exhibited partial or full cross-resistance in all six pairs. Notably, in two of the acquired cisplatin-resistant lines (41McisR and HX/155cisR) where JM216 retained activity, resistance has previously shown to be due primarily to reduced platinum uptake. In vivo, following p.o. administration using the cisplatin-sensitive murine ADJ/PC6 plasmacytoma, JM216 showed antitumor selectivity far superior to that observed for either cisplatin, carboplatin, or tetraplatin. Across four human ovarian carcinoma xenografts of widely differing sensitivity to cisplatin and carboplatin, JM216 exhibited p.o. activity, broadly comparable to that observed for i.v. administered cisplatin and carboplatin and markedly superior to i.p. administered tetraplatin. These antitumor properties suggest that JM216 provides a structural lead to platinum complexes which may circumvent transport-determined acquired resistance to cisplatin and is a suitable candidate as an p.o. administrable platinum complex for phase I clinical trial.

¹ This study was supported by grants to the Institute of Cancer Research from the Cancer Research Campaign (United Kingdom), the Medical Research Council, the Johnson Matthey Technology Centre, and Bristol-Myers Squibb Oncology.

² To whom requests for reprints should be addressed.

³ G. A. died on 3/8/93. This study is dedicated to his memory.

Received 12/18/92. Accepted 3/24/93.

This article has been cited by other articles:

				C. N. Sternberg, D. P. Petrylak, O. Sartor, J. A. Witjes, T. Demkow, J.-M. Ferrero, J.-C. Eymard, S. Falcon, F. Calabro, N. James, et al. Multinational, Double-Blind, Phase III Study of Prednisone and Either Satraplatin or Placebo in Patients With Castrate-Refractory Prostate Cancer Progressing After Prior Chemotherapy: The SPARC Trial J. Clin. Oncol., November 10, 2009; 27(32): 5431 - 5438. [Abstract] [Full Text] [PDF]

				A. D. Ricart, J. Sarantopoulos, E. Calvo, Q. S. Chu, D. Greene, F. E. Nathan, M. E. Petrone, A. W. Tolcher, and K. P. Papadopoulos Satraplatin, an Oral Platinum, Administered on a Five-day Every-Five-Week Schedule: a Pharmacokinetic and Food Effect Study Clin. Cancer Res., June 1, 2009; 15(11): 3866 - 3871. [Abstract] [Full Text] [PDF]

				H. Choy, C. Park, and M. Yao Current Status and Future Prospects for Satraplatin, an Oral Platinum Analogue Clin. Cancer Res., March 15, 2008; 14(6): 1633 - 1638. [Abstract] [Full Text] [PDF]

				J. M. Perez, L. R. Kelland, E. I. Montero, F. E. Boxall, M. A. Fuertes, C. Alonso, and C. Navarro-Ranninger Antitumor and Cellular Pharmacological Properties of a Novel Platinum(IV) Complex: trans-[PtCl2(OH)2(Dimethylamine) (Isopropylamine)] Mol. Pharmacol., April 1, 2003; 63(4): 933 - 944. [Abstract] [Full Text] [PDF]

				T. Kurata, T. Tamura, Y. Sasaki, H. Fujii, S. Negoro, M. Fukuoka, and N. Saijo Pharmacokinetic and Pharmacodynamic Analysis of Bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) Administered Once a Day for Five Consecutive Days: A Phase I Study Jpn. J. Clin. Oncol., September 1, 2000; 30(9): 377 - 384. [Abstract] [Full Text] [PDF]

				E. Fokkema, H. J.M. Groen, J. Bauer, D. R.A. Uges, C. Weil, and I. E. Smith Phase II Study of Oral Platinum Drug JM216 as First-Line Treatment in Patients With Small-Cell Lung Cancer J. Clin. Oncol., December 1, 1999; 17(12): 3822 - 3827. [Abstract] [Full Text] [PDF]

				V. M. González, M. A. Fuertes, A. Jiménez-Ruíz, C. Alonso, and J. M. Pérez The Formation of DNA Interstrand Cross-Links by a Novel Bis-[Pt2Cl4(diminazene aceturate)2]Cl4·4H2O Complex Inhibits the B to Z Transition Mol. Pharmacol., April 1, 1999; 55(4): 770 - 777. [Abstract] [Full Text]