The study outlined in this grant proposal will focus on a group of selected tetravalent platinum-based antitumor drugs. The present proposal will permit us to gain understanding of 1,2-diaminocyclohexane platinum(IV) complexes which may have actions via mechanisms other than simple reduction to their analogous 1,2-diaminocyclohexane platinum(II) complexes. Such an undertaking will involve broad aspects of biochemical, cellular and in vivo evaluation of drug pharmacology which we believe to be essential in the eventual selection of clinical drug candidates. Specifically, a series of isomeric (i.e. trans-R,R, trans- S,S and cis) 1,2-diaminocyclohexane platinum(IV) complexes with selected and specifically chosen axial and equatorial leaving ligands will be synthesized, the nature and kinetics of in vitro and in vivo transformation products of these tetravalent platinum complexes examined, the antitumor activity in vitro and in vivo against murine (e.g. L1210/0, L1210/cisplatin) and human (Brown melanoma) tumor lines determined, and potential to produce specific target organ toxicities evaluated. We believe the proposed studies will lead to a valuable understanding of the efficacy, toxicity, cellular and biochemical pharmacology of platinum(IV) complexes. The information will be essential in evaluating these complexes as a distinct class of platinum antitumor agents and in the design and development of a highly useful third-generation platinum(IV) antitumor drug.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA041581-06
Application #
3182238
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1986-05-01
Project End
1994-04-30
Budget Start
1991-05-01
Budget End
1992-04-30
Support Year
6
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Mori, A; Wu, S P; Han, I et al. (1996) In vivo antitumor activity of cis-bis-neodecanoato-trans-R,R-1, 2-diaminocyclohexane platinum(II) formulated in long-circulating liposomes. Cancer Chemother Pharmacol 37:435-44
Li, S; Khokhar, A R; Perez-Soler, R et al. (1995) Improved antitumor activity of cis-Bis-neodecanoato-trans-R,R-1,2- diaminocyclohexaneplatinum (II) entrapped in long-circulating liposomes. Oncol Res 7:611-7
Sakaguchi, Y; Stephens, L C; Makino, M et al. (1995) Apoptosis in tumors and normal tissues induced by whole body hyperthermia in rats. Cancer Res 55:5459-64
Yoshida, M; Khokhar, A R; Siddik, Z H (1994) Axial ligands and alicyclic ring size modulate the activity and biochemical pharmacology of ammine/cycloalkylamine-platinum(IV) complexes in tumor cells resistant to cis-diamminedichloroplatinum(II) or trans-1R,2R-1S,2S-diaminocyclohexanetetrachloroplatin Cancer Res 54:4691-7
Siddik, Z H; Thai, G; Yoshida, M et al. (1994) Ammine/amine platinum (II) complexes effective in vivo against murine tumors sensitive or resistant to cisplatin and tetraplatin. J Cancer Res Clin Oncol 120:571-7
Yoshida, M; Khokhar, A R; Siddik, Z H (1994) Circumvention of platinum resistance: structure-activity relationship for homologous series of ammine/amine platinum(II) complexes in L1210 cell lines. Anticancer Drug Des 9:425-34
Ohno, S; Siddik, Z H; Kido, Y et al. (1994) Thermal enhancement of drug uptake and DNA adducts as a possible mechanism for the effect of sequencing hyperthermia on cisplatin-induced cytotoxicity in L1210 cells. Cancer Chemother Pharmacol 34:302-6
Khokhar, A R; al-Baker, S; Siddik, Z H (1994) Synthesis and antitumor activity of 1,2-diaminocyclohexane platinum(IV) complexes. J Inorg Biochem 54:39-47
Yoshida, M; Khokhar, A R; Siddik, Z H (1994) Biochemical pharmacology of homologous alicyclic mixed amine platinum(II) complexes in sensitive and resistant tumor cell lines. Cancer Res 54:3468-73
Perez-Soler, R; Francis, K; al-Baker, S et al. (1994) Preparation and characterization of liposomes containing a lipophilic cisplatin derivative for clinical use. J Microencapsul 11:41-54

Showing the most recent 10 out of 62 publications