Abstract

The objective of this proposal is the further development of a multifaceted research program for studying the biochemical mechanisms of action, and the molecular basis of resistance to antitumor drugs. Initially, bleomycin and taxol will be the drugs used in our research program which includes a) in vitro biochemical studies to investigate the interaction of bleomycin with DNA and the binding of taxol to microtubules; b) preparation of radiolabeled bleomycin and taxol; c) the uptake, efflux and metabolism of these drugs in cells; d) preparation of antibodies to taxol to be used for immunofluorescent localization of the drug and radioimmunoassays; e) the preparation, transport into cells and analysis of drug-tumor specific monoclonal antibody complexes; and e) studies with new natural compounds related to taxol and synthetic taxol analogs to develop structure-activity relationships for improving the solubility and therapeutic activity of the drug. In addition, the effects of drugs are being studied in the macrophage- like cell line J774 in which functions such as phagocytosis and migration can be quantitated. Sublines of the J774 cell line that are resistant to the growth inhibitory properties of taxol and bleomycin have been isolated and are being analyzed for macrophage function, biochemical abnormalities, karyotype, cross resistance or hypersensitivity to other drugs and alterations in drug uptake. These variants plus others that are resistant to the growth-inhibitory effects of colchicine and vinblastine have double minute chromosomes. The membranes of each of these sublines contain a unique phosphoglycoprotein that is not present in the parental cell line. Studies on the biosynthesis, purification, localization and function of the phosphoglycoproteins are proposed. Antibodies prepared against the phosphoglycoprotein will be used for isolation of specific mRNA. The presence of amplified DNA sequences and their location will be probed. New drugs, preferably with unique structures, will be added to our program as will a variety of new drug-resistant cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA039821-05
Application #
3479103
Study Section
(SRC)
Project Start
1985-08-01
Project End
1992-07-31
Budget Start
1989-08-01
Budget End
1990-07-31
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost

  Institution

Name
Albert Einstein College of Medicine
Department
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461

  Publications

Mani, S; McDaid, H M; Grossman, A et al. (2007) Peripheral blood mononuclear and tumor cell pharmacodynamics of the novel epothilone B analogue, ixabepilone. Ann Oncol 18:190-5
Mani, Sridhar; Huang, Haiyan; Sundarababu, Sumathy et al. (2005) Activation of the steroid and xenobiotic receptor (human pregnane X receptor) by nontaxane microtubule-stabilizing agents. Clin Cancer Res 11:6359-69
Klein, Laura E; Freeze, B Scott; Smith 3rd, Amos B et al. (2005) The microtubule stabilizing agent discodermolide is a potent inducer of accelerated cell senescence. Cell Cycle 4:501-7
Geney, Raphael; Sun, Liang; Pera, Paula et al. (2005) Use of the tubulin bound paclitaxel conformation for structure-based rational drug design. Chem Biol 12:339-48
Ikui, Amy E; Yang, Chia-Ping Huang; Matsumoto, Tomohiro et al. (2005) Low concentrations of taxol cause mitotic delay followed by premature dissociation of p55CDC from Mad2 and BubR1 and abrogation of the spindle checkpoint, leading to aneuploidy. Cell Cycle 4:1385-8
Mani, Sridhar; McDaid, Hayley; Hamilton, Anne et al. (2004) Phase I clinical and pharmacokinetic study of BMS-247550, a novel derivative of epothilone B, in solid tumors. Clin Cancer Res 10:1289-98
Chen, Jie-Guang; Yang, Chia-Ping Huang; Cammer, Michael et al. (2003) Gene expression and mitotic exit induced by microtubule-stabilizing drugs. Cancer Res 63:7891-9
Verdier-Pinard, Pascal; Wang, Fang; Burd, Berta et al. (2003) Direct analysis of tubulin expression in cancer cell lines by electrospray ionization mass spectrometry. Biochemistry 42:12019-27
Verdier-Pinard, Pascal; Wang, Fang; Martello, Laura et al. (2003) Analysis of tubulin isotypes and mutations from taxol-resistant cells by combined isoelectrofocusing and mass spectrometry. Biochemistry 42:5349-57
Martello, Laura A; Verdier-Pinard, Pascal; Shen, Heng-Jia et al. (2003) Elevated levels of microtubule destabilizing factors in a Taxol-resistant/dependent A549 cell line with an alpha-tubulin mutation. Cancer Res 63:1207-13

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