The objective is to develop more selective treatments for neoplastic diseases based on the identification of factors which are predictive for the tumor cells' sensitivity and resistance to antimetabolites. Initial studies will focus on the identification of cellular determinants of response to 1-Beta-D-arabinofuranosylcytosine (araC), and on understanding the role metabolic modulators such as dL-leucovorin (dL-CF) play in selectively alterating the therapeutic efficacy of 5-fluorouracil (FUra) and 5-fluorodeoxyuridine (FdUrd). The role of cisplatin in enhanceing the therapeutic efficacy of fluoropyrimidines + dL-CF and araC will also be evaluated. For studies involving araC, mouse leukemia L1210 transplanted intraperitoneally and subcutaneously, mouse colon carcinoma no. 26 transplanted s.c. and the lymphoid tumor P-388 transplanted i.p. will be used, based on their differential sensitivity to araC. Determinations with fluoropyrimidines will be carried out in cells with differential sensitivity and with different intracellular concentrations of thymidylate synthase and folate cofactor pools. These cell lines include leukemia L1210, P-1798 lymphosarcoma, rat colon adenocarcinoma (both with high pre-existing pools), human colon carcinoma no. 205 and B-16 melanoma containing relatively lower folate pools. Specific studies with araC include: 1) the simultaneous quantitation of araCTP pools and retention and incorporation of araC into DNA of tumors and of bone marrow and intestinal mucosa; 2) assessment of the in vivo effects of cis-DDP on araC determinants of response. These studies will compare prolonged continuous infusions of low doses vs short infusions of high doses. Studies with fluoropyrimidine will focus on the identification of optimal conditions for their potentiation by folates. The existence of a possible relationship between a defined plasma concentration of folates, intracellular folate pools and inhibition and recovery of dTMP-synthase in normal and tumor cells will be examined. The studies should provide fundamental information concerning the biochemical and pharmacological basis of drug action in vivo and the results obtained should allow the design of improved clinical protocols and the verification of response in patients with cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA018420-12
Application #
3164945
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1979-07-01
Project End
1990-09-30
Budget Start
1988-12-01
Budget End
1990-09-30
Support Year
12
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263
van Laar, J A; Durrani, F A; Rustum, Y M (1993) Antitumor activity of the weekly intravenous push schedule of 5-fluoro-2'-deoxyuridine +/- N-phosphonacetyl-L-aspartate in mice bearing advanced colon carcinoma 26. Cancer Res 53:1560-4
Zhang, Z G; Malmberg, M; Yin, M B et al. (1993) Isolation and characterization of a human ileocecal carcinoma cell line (HCT-8) subclone resistant to fluorodeoxyuridine. Biochem Pharmacol 45:1157-64
Rustum, Y M; Raymakers, R A (1992) 1-Beta-arabinofuranosylcytosine in therapy of leukemia: preclinical and clinical overview. Pharmacol Ther 56:307-21
Yin, M B; Rustum, Y M (1991) Comparative DNA strand breakage induced by FUra and FdUrd in human ileocecal adenocarcinoma (HCT-8) cells: relevance to cell growth inhibition. Cancer Commun 3:45-51
Cullinan, E B; Gawron, L S; Rustum, Y M et al. (1990) Topoisomerase II-mediated DNA damage of episomes in tumor-bearing mice. Cancer Res 50:6154-7
Slocum, H K; Malmberg, M; Greco, W R et al. (1990) The determination of growth rates of individual colonies in agarose using high-resolution automated image analysis. Cytometry 11:793-804
Yin, M B; Bankusli, I; Frank, C et al. (1990) Modulation of doxorubicin-induced DNA lesions by verapamil, DMDP and dipyridamole in resistant P388 cell lines. Anticancer Res 10:327-32
Mini, E; Trave, F; Rustum, Y M et al. (1990) Enhancement of the antitumor effects of 5-fluorouracil by folinic acid. Pharmacol Ther 47:1-19
Bankusli, I; Yin, M B; Mazzoni, A et al. (1989) Enhancement of adriamycin-induced cytotoxicity by increasing retention and inhibition of DNA repair in DOX-resistant P388 cell lines with new calcium channel blocker, DMDP. Anticancer Res 9:567-74
Rustum, Y M (1989) Toxicity and antitumor activity of 5-fluorouracil in combination with leucovorin. Role of dose schedule and route of administration of leucovorin. Cancer 63:1013-7

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