A Phase I/pilot study of sequential doxorubicin/vinorelbine: effects on p53 and microtubule-associated protein 4.
OBJECTIVE
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.


METHODS
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.
Bash-Babula
Judy
J
Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick 08901, USA.
Toppmeyer
Deborah
D
Labassi
Marie
M
Reidy
Janice
J
Orlick
Michelle
M
Senzon
Rachelle
R
Alli
Elizabeth
E
Kearney
Thomas
T
August
David
D
Shih
Weichung
W
Yang
Jin-Ming
JM
Hait
William N
WN
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005334:Fever / Q000139:chemically induced; D006801:Humans; D007150:Immunohistochemistry; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009367:Neoplasm Staging; D009503:Neutropenia / Q000139:chemically induced; D010865:Pilot Projects; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000077235:Vinorelbine; D014839:Vomiting / Q000139:chemically induced
D008869:Microtubule-Associated Proteins; D016159:Tumor Suppressor Protein p53; D014747:Vinblastine; D004317:Doxorubicin; D000077235:Vinorelbine