Oral gossypol in the treatment of patients with refractory metastatic breast cancer: A phase I/II clinical trial

Gossypol has demonstrated in vitro effects on cell cycle regulation and ant i-tumor activity against mammary carcinoma cell lines. This Phase I/II stud y assesses both the effect of gossypol on cell cycle regulatory proteins in vivo and the clinical effect. Twenty women with refractory metastatic brea st cancer received oral gossypol at daily doses between 30 and 50 mg per da y. Gossypol plasma levels were measured (n = 8) and the modulation of the r etinoblastoma (Rb) gene protein and Cyclin D1 was assessed by serial biopsi es (n = 4). Grade I-II toxicities with gossypol treatment included nausea i n 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 h ad a minor response and two patients had stable disease with > 50 decline i n serial assessments of the serum tumor markers. Immunohistochemical analys is of cyclin D1 and Rb expression in serial biopsies of four patients revea led both a concurrent decrease in cyclin D1 expression and an increase in n uclear Rb expression in three patients. The maximal tolerated dose (MTD) of gossypol was 40 mg/day. Gossypol appears to affect the expression of Rb pr otein and cyclin D1 in breast cancer metastases at doses achievable, yet ha d negligible antitumor activity against anthracycline and taxane refractory metastatic breast cancer. The cell cycle regulatory effects of gossypol su ggest a potential role for gossypol as a modulating agent in conjunction wi th other cell cycle specific compounds.