ABSTRACT
CGS 16949A is a new, nonsteroidal competitive inhibitor of the aromatase enzyme. In this Phase I trial, 16 heavily pretreated postmenopausal patients with metastatic breast cancer were treated with escalating doses of CGS 16949A from 0.6 to 16 mg total daily oral dose. No hematologic, biochemical, or significant clinical toxicity was encountered. Endocrinologic and pharmacologic data were available from 12 of these patients. Maximum inhibition of estrogen biosynthesis was observed at a dose of 2 mg CGS 16949A daily. At this dose, the inhibition of estrogen biosynthesis was equivalent to 1000 mg aminoglutethimide (AG). The fall in plasma and urinary estrogens without a concomitant drop in androgens confirmed the specific blockade of aromatase activity. At doses of 4 to 16 mg daily, CGS 16949A appeared to inhibit the C21-hydroxylase enzyme as well. The t1/2 of CGS 16949A in the circulation was 10.5 hours. Of 16 evaluable patients there were two partial responses and seven patients with stable disease.
Subject(s)
Antineoplastic Agents/therapeutic use , Aromatase Inhibitors , Breast Neoplasms/drug therapy , Imidazoles/therapeutic use , Menopause , Nitriles/therapeutic use , Adult , Aged , Androgens/blood , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Aromatase/administration & dosage , Aromatase/adverse effects , Breast Neoplasms/blood , Breast Neoplasms/pathology , Drug Administration Schedule , Drug Evaluation , Estrogens/blood , Fadrozole , Female , Humans , Imidazoles/administration & dosage , Imidazoles/adverse effects , Lymphatic Metastasis , Menopause/blood , Middle Aged , Nitriles/administration & dosage , Nitriles/adverse effectsABSTRACT
Hypercalcemia is a common and serious complication of neoplastic disease. It may occur in association with a variety of tumors and usually indicates a lack of tumor control. Early symptoms are nonspecific, involving several organ systems in a syndrome that may progress rapidly to death. The pathophysiology of hypercalcemia is complex and not fully understood. Research continues on local mechanisms of bone destruction at sites of bone metastases and the identification of humoral tumor-derived osteolytic factors. The therapeutic approach to hypercalcemia should be sequential, dictated more by clinical symptoms than by absolute calcium levels. The diversity of measures and agents used in the therapy of hypercalcemia of malignancy reflects the multiple mechanisms involved. The therapeutic maneuvers outlined usually yield temporary success and must be accompanied by specific antitumor therapy, the ultimate treatment for the hypercalcemia of neoplastic disease.
