The treatment of cancer patients with chemotherapy is often empirical. Even the most active drugs produce meaningful responses in the minority of patients. As a result, many patients are exposed to and suffer the side effects of toxic medications without reaping the benefits. For example, taxanes, such as paclitaxel and docetaxel, and vinca alkaloids, such as vinorelbine, and vinblastine, are amongst the most active drugs in the treatment of common malignancies including breast, lung, and prostate. Yet, less than 50 percent of patients respond to these individual agents. Despite this, clinicians have no way of predicting who will respond and who will not. Mutations in p53 occur in approximately 50 percent of human cancers. Recent studies indicate that p53 mutations affect the sensitivity to cancer chemotherapeutic drugs. In studying the mechanism(s) underlying this observation, we found that increased expression of microtubule associated protein 4 (MAP4), which occurs when p53 is transcriptionally silent, is associated with increased sensitivity to paclitaxel and decreased sensitivity to vinca alkaloids. Using murine fibroblasts transfected with MAP4, we demonstrated that these changes in drug sensitivity were reproduced by overexpression of the MAP4 protein. MAP4 overexpression resulted in alterations in drug-induced apoptosis and cell-cycle arrest. Immunofluorescent staining of the microtubule network revealed that cells with increased MAP4 protein expression contained greater polymerized microtubules and bound more fluoresceinated paclitaxel than controls. Since MAP4 catalyzes and stabilizes the polymerization of microtubules, overexpression of this gene provides a credible mechanism to explain the sensitivity to microtubule-active drugs in the presence of mutant p53. Therefore, we propose to study the implications of these observations by analyzing the effects of p53 function on MAP4 overexpression and drug sensitivity in human cancer cell lines and following wild type p53 induction by DNA damage. We will capitalize on our findings to design more rationale uses of antimitotic drugs in combination with DNA damaging agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078695-04
Application #
6513152
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Fu, Yali
Project Start
1999-07-12
Project End
2004-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
4
Fiscal Year
2002
Total Cost
$162,713
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
622146454
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Alli, Elizabeth; Yang, Jin-Ming; Ford, James M et al. (2007) Reversal of stathmin-mediated resistance to paclitaxel and vinblastine in human breast carcinoma cells. Mol Pharmacol 71:1233-40
Nayak, Mamatha S; Yang, Jin-Ming; Hait, William N (2007) Effect of a single nucleotide polymorphism in the murine double minute 2 promoter (SNP309) on the sensitivity to topoisomerase II-targeting drugs. Cancer Res 67:5831-9
Alli, E; Yang, J-M; Hait, W N (2007) Silencing of stathmin induces tumor-suppressor function in breast cancer cell lines harboring mutant p53. Oncogene 26:1003-12
Hait, William N; Yang, Jin-Ming (2006) The individualization of cancer therapy: the unexpected role of p53. Trans Am Clin Climatol Assoc 117:85-101; discussion 101
Hait, William N; Rubin, Eric; Goodin, Susan (2003) Tubulin-targeting agents. Cancer Chemother Biol Response Modif 21:41-67
Bash-Babula, Judy; Toppmeyer, Deborah; Labassi, Marie et al. (2002) A Phase I/pilot study of sequential doxorubicin/vinorelbine: effects on p53 and microtubule-associated protein 4. Clin Cancer Res 8:1057-64
Alli, Elizabeth; Bash-Babula, Judy; Yang, Jin-Ming et al. (2002) Effect of stathmin on the sensitivity to antimicrotubule drugs in human breast cancer. Cancer Res 62:6864-9
Hait, William N; Rubin, Eric; Goodin, Susan (2002) Tubulin-targeting agents. Cancer Chemother Biol Response Modif 20:71-97
Hait, W N (2001) The prognostic and predictive values of ECD-HER-2. Clin Cancer Res 7:2601-4
Hait, W N; Rubin, E; Goodin, S (2001) Tubulin targeting agents. Cancer Chemother Biol Response Modif 19:59-83

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