cyclin-d1 and Nausea

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.

Topics: Administration, Oral; Adult; Aged; Breast Neoplasms; Cell Cycle; Cyclin D1; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Fatigue; Female; Gossypol; Humans; Immunohistochemistry; Middle Aged; Nausea; Retinoblastoma Protein; Taste Disorders; Treatment Outcome

Malignant melanoma is a relatively rare but potentially aggressive tumor in children and adolescents. We report the case of a metastatic malignant melanoma in a 17-year-old girl, first diagnosed on cytological features of a fine-needle lymph node aspiration and then histologically confirmed by both examination of the metastatic adenopathy and a clinically harmless skin lesion of the scalp, which harbored focal microscopic pattern of melanoma. A fluorescent in situ hybridization study revealed that both metastatic and primary cutaneous tumours contained the same and pejorative chromosomal aberration consisting in CCND1 amplification (11q13). This observation raises actual limits and challenges in the fields of diagnosis and treatment of fast-killing melanomas.

Topics: Adolescent; Antibodies, Monoclonal; Antineoplastic Agents, Alkylating; Back Pain; Combined Modality Therapy; Cyclin D1; Dacarbazine; Drug Resistance, Neoplasm; Fatal Outcome; Female; Gene Amplification; Head and Neck Neoplasms; Humans; Immunotherapy; In Situ Hybridization, Fluorescence; Ipilimumab; Lymphatic Metastasis; Melanoma; Nausea; Neoplasm Proteins; Neoplasms, Second Primary; Nevus; Osteolysis; Scalp; Skin Neoplasms; Weight Loss