While the anthracycline antitumor antibiotic adriamycin (doxorubicin) retains its premier position in clinical cancer chemotherapy, its toxicity and lack of effectiveness against some of the more common advanced carcinomas continue to emphasize the need for anthracycline analogs with improved therapeutic efficacy. Discounting the conventional view that anthracycline antitumor action is tied mechanistically to drug-DNA binding, we have successfully developed novel DNA-nonbinding adriamycin analogs from concept to clinic; these include N-(trifluoroacetyl)adriamycin-14-valerate (AD 32), which has gone through extensive Phase I-II studies, and N-(trifluoroacetyl)adriamycin-14-0-emiadipate(AD 143), which is expected shortly to enter clinical trials. Recently we have found lipophilic N-alkyladriamycin derivatives with significant therapeutic superiority to adriamycin in experimental system, despite poor DNA-binding; and with mechanistic properties differing from adriamycin and from AD 32/AD 143. In an integrated program of chemical and biological studies, we plan to thoroughly explore the structure-activity relationships among N-alkyl- and corresponding 14-acyl-substituted anthracyclines, including the effect of combining N-alkylation with N-trifluoroacetylation. The synthesis and properties of novel 7-0-(4'-N-alkyl)morpholinylanthracyclinone analogs will be explored. Further studies probing structure-activity correlations among analogs related to AD 32 and AD 143 are proposed; studies will also be directed towards linking AD 143 with tumor-specific monoclonal antibodies. Based on the promise of some recently obtained analogs, a number of anthracyclinone furanoside derivatives, with azido, amino, or desamino functionality in the sugar, will be studied as glycoside ring-contracted variants of parent anthracycline antibiotics. Various aminoglycoside anthracyclines and analogs will be used for conversion to nitrosoureas in a rational attempt to obtain agents with dual chemotherapeutic and/or radiosensitizing properties. As before, chemical studies will be augmented by a range of appropriate biological studies aimed at exploring the therapeutic potential of the semisynthetically-derived target compounds. In vitro studies will include growth-inhibition assays against sensitive and resistant lymphoid-derived cell lines and effects of agents on macro-molecule synthesis. In vivo evaluation will include determination of the antitumor effects of target compounds on various murine solid tumor models, as well as in leukemia systems; nitrosoureas will additionally be studied for possible drug radiation synergy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA037082-05
Application #
3174767
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1983-07-01
Project End
1990-01-31
Budget Start
1988-02-01
Budget End
1989-01-31
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Chuang, L F; Kung, H F; Israel, M et al. (1992) Activation of human leukemia protein kinase C by tumor promoters and its inhibition by N-trifluoroacetyladriamycin-14-valerate (AD 32). Biochem Pharmacol 43:865-72
Lothstein, L; Sweatman, T W; Dockter, M E et al. (1992) Resistance to N-benzyladriamycin-14-valerate in mouse J774.2 cells: P-glycoprotein expression without reduced N-benzyladriamycin-14-valerate accumulation. Cancer Res 52:3409-17
Lothstein, L; Wright, H M; Sweatman, T W et al. (1992) N-benzyladriamycin-14-valerate and drug resistance: correlation of anthracycline structural modification with intracellular accumulation and distribution in multidrug resistant cells. Oncol Res 4:341-7
Sweatman, T W; Seshadri, R; Israel, M (1990) Metabolism and elimination of rhodamine 123 in the rat. Cancer Chemother Pharmacol 27:205-10
Bodley, A; Liu, L F; Israel, M et al. (1989) DNA topoisomerase II-mediated interaction of doxorubicin and daunorubicin congeners with DNA. Cancer Res 49:5969-78
Israel, M; Sweatman, T W; Seshadri, R et al. (1989) Comparative uptake and retention of adriamycin and N-benzyladriamycin-14-valerate in human CEM leukemic lymphocyte cell cultures. Cancer Chemother Pharmacol 25:177-83
Zhao, F K; Chuang, L F; Israel, M et al. (1989) Adriamycin interacts with diacylglycerol to inhibit human leukemia protein kinase C. Anticancer Res 9:225-9
Zhao, F K; Chuang, L F; Israel, M et al. (1989) Cremophor EL, a widely used parenteral vehicle, is a potent inhibitor of protein kinase C. Biochem Biophys Res Commun 159:1359-67
Lameh, J; Chuang, R Y; Israel, M et al. (1989) Nucleoside uptake and membrane fluidity studies on N-trifluoroacetyladriamycin-14-O-hemiadipate-treated human leukemia and lymphoma cells. Cancer Res 49:2905-8
Ganapathi, R; Grabowski, D; Sweatman, T W et al. (1989) N-benzyladriamycin-14-valerate versus progressively doxorubicin-resistant murine tumours: cellular pharmacology and characterisation of cross-resistance in vitro and in vivo. Br J Cancer 60:819-26

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