(taken from investigator s abstract) Given that taxanes and vinca alkaloids are substrates for the mdr1 gene product, P-glycoprotein (Pgp), and given that Pgp is not expressed in all clinical tumor specimens, the investigator postulates that other mechanisms of resistance to these classes of drugs may be expressed. Tubulins are the targets of the taxanes and vinca alkaloids. Accordingly, the goal of this revised application is to explore other mechanisms of resistance to these agents, with a focus on tubulin genes. In support of this idea, some cell lines selected for resistance to taxol express altered beta-tubulin. The investigator therefore postulates that alterations in tubulin isoform expression, especially changes in relative abundance, are responsible for this form of resistance, and proposes 4 specific aims to test this hypothesis: (1) to determine tubulin isoform expression in non-MDR models of resistance to tubulin-targeted cytotoxins in leukemia, breast and ovarian carcinoma; (2)to study the effects of altered tubulin gene expression on drug sensitivity and microtubule assembly dynamics in transfected cells; (3) to modulate drug sensitivity by down-regulation of specific tubulin gene expression with antisense constructs and oligonucleotides; and (4) to study tubulin isoform expression in tumor specimens obtained from patients before and after therapy with taxanes or vinca alkaloids.
| Sale, Sanja; Sung, Raphael; Shen, Peidong et al. (2002) Conservation of the class I beta-tubulin gene in human populations and lack of mutations in lung cancers and paclitaxel-resistant ovarian cancers. Mol Cancer Ther 1:215-25 |
| Dumontet, C; Sikic, B I (1999) Mechanisms of action of and resistance to antitubulin agents: microtubule dynamics, drug transport, and cell death. J Clin Oncol 17:1061-70 |
| Dumontet, C; Duran, G E; Steger, K A et al. (1996) Differential expression of tubulin isotypes during the cell cycle. Cell Motil Cytoskeleton 35:49-58 |
