Folate metabolism and physiology continue to represent attractive targets for chemotherapeutic intervention. This is clearly demonstrated by the recent development of new classes of folate analogues targeted to folate- dependent biosynthetic reactions that have entered clinical trial. The applicant's own work with his collaborators has resulted in the design of a new 4-amino-folate analogue, edatrexate, with significantly improved therapeutic activity against certain solid tumors in patients compared to methotrexate in advanced clinical development. The studies proposed extend this work and seek further improvement in the treatment of human cancer with new, more efficacious folate analogues, new or optimized regimens of therapy utilizing tumor-specific targeting or seeking synergistic combinations and by circumvention of acquired resistance. The underlying basis for these approaches stems from the applicant's identification in tumors of a specific route of mediated membrane transport and a distinct folylpolyglutamate synthetase that mediate 4-aminofolyl polyglutamate accumulation that are major determinants of therapeutic selectivity of these analogues. New studies will pursue in depth knowledge of these determinants in parental and antifolate-resistant tumor cells at the level of their functional and structural biochemistry, energetics and regulation of gene expression. The latter addresses the unique ontogenetics of these determinants in tumor cells compared to their functional counterparts in normal proliferative tissues that are sites of drug limiting toxicity for these antifolates. Work will also continue in tumor cells on the ATP- dependent efflux route for folate analogues and on folyl and antifolyl polyglutamate transport and turnover in lysosomes, focusing on the molecular properties of the transport system in each case. The mechanism of activation of lysosomal folyl polyglutamate hydrolase by endogenous reduced sulfhydryl compounds will also be examined. All of these studies present further opportunities for modulation therapies that achieve favorable intratumoral pharmacokinetics for new folate analogues including those targeted at sites other than DHFR.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA056517-06
Application #
2712656
Study Section
Special Emphasis Panel (SRC (88))
Program Officer
Johnson, George S
Project Start
1993-08-01
Project End
2000-05-31
Budget Start
1998-06-01
Budget End
1999-05-31
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Sirotnak, F M; She, Yuhong; Khokhar, Nushmia Z et al. (2004) Microarray analysis of prostate cancer progression to reduced androgen dependence: studies in unique models contrasts early and late molecular events. Mol Carcinog 41:150-63
Sirotnak, Francis M (2003) Studies with ZD1839 in preclinical models. Semin Oncol 30:12-20
She, Yuhong; Lee, Fei; Chen, Jing et al. (2003) The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 selectively potentiates radiation response of human tumors in nude mice, with a marked improvement in therapeutic index. Clin Cancer Res 9:3773-8
Masumoto, Naoko; Chen, Jing; Sirotnak, F M (2002) Regulation of transcription of the murine gamma-glutamyl hydrolase gene. Delineation of core promoter A and the role of LYF-1, E2F and ETS-1 in determining tumor-specific expression. Gene 291:169-76
Sirotnak, Francis M; She, Yohung; Lee, Fei et al. (2002) Studies with CWR22 xenografts in nude mice suggest that ZD1839 may have a role in the treatment of both androgen-dependent and androgen-independent human prostate cancer. Clin Cancer Res 8:3870-6
Khokhar, N Z; She, Y; Rusch, V W et al. (2001) Experimental therapeutics with a new 10-deazaaminopterin in human mesothelioma: further improving efficacy through structural design, pharmacologic modulation at the level of MRP ATPases, and combined therapy with platinums. Clin Cancer Res 7:3199-205
Masumoto, N; Esaki, T; Sirotnak, F M (2001) Additional organizational features of the murine gamma-glutamyl hydrolase gene. Two remotely situated exons within the complement C3 gene locus encode an alternate 5' end and proximal ORF under the control of a bidirectional promoter. Gene 268:183-94
Sirotnak, F M; Zakowski, M F; Miller, V A et al. (2000) Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 6:4885-92
Fritz, F; Chen, J; Hayes, P et al. (2000) Molecular cloning of the murine cMOAT ATPase. Biochim Biophys Acta 1492:531-6
Sirotnak, F M; Sepp-Lorenzino, L; Kohl, N E et al. (2000) A peptidomimetic inhibitor of ras functionality markedly suppresses growth of human prostate tumor xenografts in mice. Prospects for long-term clinical utility. Cancer Chemother Pharmacol 46:79-83

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