title: Oral gossypol in the treatment of patients with refractory metastatic breast cancer: a phase I/II clinical trial.
abstract: Gossypol has demonstrated in vitro effects on cell cycle regulation and anti-tumor activity against mammary carcinoma cell lines. This Phase I/II study assesses both the effect of gossypol on cell cycle regulatory proteins in vivo and the clinical effect. Twenty women with refractory metastatic breast cancer received oral gossypol at daily doses between 30 and 50 mg per day. Gossypol plasma levels were measured (n = 8) and the modulation of the retinoblastoma (Rb) gene protein and Cyclin D1 was assessed by serial biopsies (n = 4). Grade I-II toxicities with gossypol treatment included nausea in 30% of patients, fatigue 15%, emesis 15%, altered taste sensation 15% and diarrhea in 10% of patients. Two of the three patients receiving 50 mg/day experienced dose limiting dermatologic toxicity (grade III). One patient had a minor response and two patients had stable disease with > 50% decline in serial assessments of the serum tumor markers. Immunohistochemical analysis of cyclin D1 and Rb expression in serial biopsies of four patients revealed both a concurrent decrease in cyclin D1 expression and an increase in nuclear Rb expression in three patients. The maximal tolerated dose (MTD) of gossypol was 40 mg/day. Gossypol appears to affect the expression of Rb protein and cyclin D1 in breast cancer metastases at doses achievable, yet had negligible antitumor activity against anthracycline and taxane refractory metastatic breast cancer. The cell cycle regulatory effects of gossypol suggest a potential role for gossypol as a modulating agent in conjunction with other cell cycle specific compounds.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: C
authors.initials: C
authors.lastname: Van Poznak
authors.forename: A D
authors.initials: AD
authors.lastname: Seidman
authors.forename: M M
authors.initials: MM
authors.lastname: Reidenberg
authors.forename: M M
authors.initials: MM
authors.lastname: Moasser
authors.forename: N
authors.initials: N
authors.lastname: Sklarin
authors.forename: K
authors.initials: K
authors.lastname: Van Zee
authors.forename: P
authors.initials: P
authors.lastname: Borgen
authors.forename: M
authors.initials: M
authors.lastname: Gollub
authors.forename: D
authors.initials: D
authors.lastname: Bacotti
authors.forename: T J
authors.initials: TJ
authors.lastname: Yao
authors.forename: R
authors.initials: R
authors.lastname: Bloch
authors.forename: M
authors.initials: M
authors.lastname: Ligueros
authors.forename: M
authors.initials: M
authors.lastname: Sonenberg
authors.forename: L
authors.initials: L
authors.lastname: Norton
authors.forename: C
authors.initials: C
authors.lastname: Hudis
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D002453:Cell Cycle / Q000187:drug effects*; D019938:Cyclin D1 / Q000032:analysis / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006072:Gossypol / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D013651:Taste Disorders / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D016160:Retinoblastoma Protein; D019938:Cyclin D1; D006072:Gossypol