Abstract. Approximately two-thirds ofpatients who receive the anticancer drug gallium nitrate develop mild hypocalcemia. To evaluate the mechanism of druginduced hypocalcemia, we tested the effects of gallium nitrate upon in vitro release of "5Ca"+ from explanted fetal rat bones. The drug significantly inhibited 45Ca`+ release in response to stimulation with both parathyroid hormone and a lymphokine preparation with osteoclast activating factor activity. The inhibitory effects on bone resorption were both time-and dose-dependent. Later, in a pilot study, we treated 10 patients who had cancerrelated hypercalcemia with gallium nitrate administered by continuous infusion. All patients responded by a reduction of total serum calcium to normal or subnormal concentrations (13.8±1.05 mg/dl, mean±SD pretreatment, to 8.03±1.03 mg/dl, mean posttreatment nadir). Our results indicate that gallium nitrate effectively treats cancer-related hypercalcemia and that it probably acts by inhibiting calcium release from bone.

Previous trials of gallium nitrate (NSC‐15200) showed that bolus administration produced dose‐limiting nephrotoxicity without substantial antitumor activity. As an effort to increase the therapeutic index of this compound and to establish a satisfactory out‐patient schedule, the authors evaluated the effects of gallium nitrate administered as a continuous infusion in patients with advanced malignant lymphoma. In an initial Phase I trial, four dose levels which ranged from 200 to 400 mg/m2/day in 27 patients were studied. Nausea which impaired oral hydration was found to be dose‐limiting. A dose of 300 mg/ m2/day was chosen for extended Phase II evaluation and 37 additional patients were entered into the study at that dose level. Overall, 16 of 47 patients (34%) who had bi‐dimensionally measurable parameters of disease achieved major antitumor responses (six of 15 with diffuse “histiocytic” lymphoma, five of ten with diffuse poorly‐differentiated lymphocytic lymphoma, two of five with nodular poorly‐differentiated lymphocytic lymphoma, and three of 17 with Hodgkin's disease). The median duration of response was 2.5 months. Only 8% of patients who received 300 mg/m2/day developed an increase in serum creatinine concentration >1.1 mg/dl over baseline values. Hypocalcemia occurred in two‐thirds of patients. Other toxic effects, including paresthesiae, diarrhea, and hearing loss, were noted in <5% of patients. There was minimal myelosuppression. The authors conclude that gallium nitrate administered as a continuous infusion for seven days at 300 mg/m2/day is well‐tolerated and effective treatment for patients with advanced malignant lymphoma. Outpatient administration using portable infusion pumps is safe and practical. Further evaluation of the drug administered as a constant infusion is indicated in patients with other neoplastic diseases.

Homoharringtonine (HHT) is a new plant alkaloid originally isolated in the People's Republic of China. Preliminary studies have suggested antitumor activity in several neoplastic diseases. We treated 49 patients with relapsed or resistant acute leukemia with escalating doses of homoharringtonine administered by continuous infusion. Three dose levels were examined: 5 mg/m2 for seven days, 7 mg/m2 for seven days, and 5 mg/m2 for nine days. Of 28 patients with acute nonlymphoblastic leukemia who received cumulative doses of 45 to 49 mg/m2, seven patients (25%) achieved complete remission. Four of these remissions occurred in a subset of ten patients previously resistant to two or more induction attempts with conventional chemotherapy. There were no remissions in three patients with secondary leukemia or in seven patients with acute lymphoblastic leukemia. Reversible hypotension, fluid retention, diarrhea, and tumor lysis syndrome were the major toxic effects of this treatment. Our results indicate that homoharringtonine is an effective new drug for the treatment of acute nonlymphoblastic leukemia and that this drug does not share cross-resistance with conventional antileukemic agents. The recommended dose is 5 mg/m2/d administered by continuous infusion for nine days.

No abstract