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A Phase I/pilot study of sequential doxorubicin/vinorelbine: effects on p53 and microtubule-associated protein 4
Judy Bash-Babula1, Deborah Toppmeyer, Marie Labassi
1Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick 08901, USA.
Purpose:
Few molecular determinants of sensitivity to cancer chemotherapy exist. In experimental systems, p53 regulates the sensitivity to antimicrotubule drugs through its effect on microtubule-associated protein 4 (MAP4). MAP4 is the major microtubule-associated protein in nonneuronal tissues and promotes microtubule polymerization. We reported that wild-type p53 induction by doxorubicin in C127 breast cancer cells repressed MAP4, decreased microtubule polymerization, and increased Vinca alkaloid sensitivity. The goals of this Phase I/pilot clinical trial were to determine: (a) the safety of delivering a DNA-damaging agent (doxorubicin) followed in sequence by treatment with an antimicrotubule drug (vinorelbine); and (b) the feasibility of detecting activation of p53 and repression of MAP4 in patients' tissues.
Experimental Design:
Peripheral blood mononuclear cells (PBMNCs) and tumor were obtained from 16 women with locally advanced (stage IIIb) or metastatic (stage IV) breast cancer before doxorubicin treatment and immediately before treatment with vinorelbine 24 or 48 h later.
Results:
After doxorubicin treatment, p53 increased in 12 of 14 PBMNC and 4 of 10 tumor samples. Changes in MAP4 were variable; however, in samples in which p53 was induced, MAP4 decreased in 7 of 12 PBMNC and 3 of 4 breast cancer specimens. Immunohistochemistry confirmed lower MAP4 expression in tumor cells after doxorubicin treatment. Seven of 16 patients had a partial response, and treatment was well tolerated.
Conclusions:
These data demonstrate the ability to detect the activation of p53 and the repression of MAP4 in normal and malignant tissues in patients treated with a DNA-damaging agent, and that an antimicrotubule drug can be administered safely at a time when cells may be more sensitive to treatment.
Insights
This study shows that doxorubicin can activate p53 and decrease MAP4 in breast cancer patients, making them more sensitive to vinorelbine. The combined treatment was safe and feasible to monitor molecular changes.
Area of Science:
- Oncology
- Molecular Biology
- Clinical Trials
Background:
- Few molecular factors predict cancer chemotherapy sensitivity.
- p53 influences sensitivity to antimicrotubule drugs via microtubule-associated protein 4 (MAP4).
- Experimental data show wild-type p53 induction represses MAP4, reducing microtubule polymerization and increasing sensitivity to Vinca alkaloids.
Purpose of the Study:
- To assess the safety of sequential doxorubicin and vinorelbine treatment in breast cancer patients.
- To determine the feasibility of detecting p53 activation and MAP4 repression in patient tissues.
- To explore the molecular mechanisms underlying chemotherapy sensitivity.
Main Methods:
- Phase I/pilot clinical trial involving 16 women with advanced or metastatic breast cancer.
- Doxorubicin administered, followed by vinorelbine 24 or 48 hours later.
- Peripheral blood mononuclear cells (PBMNCs) and tumor biopsies collected pre-treatment and pre-vinorelbine for molecular analysis (p53, MAP4).
Main Results:
- p53 activation detected in 12/14 PBMNCs and 4/10 tumors post-doxorubicin.
- MAP4 decreased in PBMNCs (7/12) and tumors (3/4) where p53 was induced.
- Sequential treatment was well-tolerated, with 7/16 patients achieving a partial response.
Conclusions:
- p53 activation and MAP4 repression can be detected in patients receiving DNA-damaging agents.
- Sequential administration of antimicrotubule drugs is safe and feasible.
- These findings support the potential for targeted chemotherapy based on molecular determinants of sensitivity.