Preparations of human peripheral mononuclear leukocytes, containing over 85% lymphocytes, specifically bound glucagon and insulin. Binding of physiological concentrations of both hormones was seen to be substantially diminished when cells were derived from either adult-type diabetics or individuals with a unilateral genetic history of diabetes.
In order to assess blood factors which might explain why some cigarette smokers develop airflow obstruction while others do not, we compared two groups of PiM phenotype volunteers matched for age, sex and total pack-years of cigarette smoking; one group had airflow obstruction and the other did not. Functional levels of alpha-2-macroglobulin (alpha-2-M) and alpha-1-protease inhibitor (alpha-1-PI) were separately assessed by a protease binding procedure. Neutrophils were isolated from blood by counterflow centrifugation, and their elastase content was assayed with 3H-elastin-SDS (sodium dodecyl sulfate). The obstructed and nonobstructed groups were not different with respect to functional or immunoreactive levels of alpha-1-PI and alpha-2-M or elastase levels in their neutrophils. We do not find imbalances of circulating elastase or antielastase levels in PiM phenotype smokers with airflow obstruction.
Thirty-five patients with metastatic malignant melanoma underwent treatment with chlorozotocin administered as a single dose of 120 mg/m2 by means of rapid intravenous infusion every six weeks. There were 1 complete and 4 partial remissions with an overall response rate of 14%. The median duration of response was 18 weeks; the patient in complete remission continues disease-free in excess of 42 weeks. The sites of response included: lung, 2; subcutaneous, 2; and lymph node, 1. There was minimal myelotoxicity: for the first cycle, the median white blood cell count nadir was 5400/mm3, and the platelet nadir was 210,000/mm3. No evidence of cumulative platelet toxicity was observed. Chlorozotocin is active against metastatic melanoma to the same degree as other chloroethylnitrosoureas in clinical use, hut without causing bone marrow toxicity. These data suggest that chlorozotocin should he evaluated in combination with other agents active against melanoma.Cancer 46:1544 -1547, 1980.EW CHEMOrHERAPEUTIC AGENTS POSSeSS any F significant therapeutic activity against disseminated malignant melanoma. DTIC has been the most widely studied. A review of ten separate studies of this drug, showed that objective partial remissions were achieved in 205 of 851 cases (24%), although the range of response rates in these studies varied from 8% to 31%.4 However, the remissions were of modest duration (median duration, about six months in several studies), and survival time still poor (median survival time, about 11The nitrosoureas have been extensively evaluated in the treatment of melanoma; objective response rates of 15% have been achieved with BCNU, CCNU, and methyl-CCNU (range; 5-28%). There is no evidence that there is any consistent or clinically significant difference between these three agents.'Chlorozotocin is a chloroethylnitrosourea which was initially selected for clinical development because it produced curative antitumor activity against the L1210 leukemia system at dosages which produced little or no bone marrow toxicity, in contrast to CCNU or BCNU.3 Chemically, chlorozotocin produces twice the in vitro alkylating activity of BCNU at equimolar concentrations. As in the animal studies, recently completed Phase 1 clinical trials have demonstrated that this bone marrow sparing effect of chlorozotocin is relative, and thrombocytopenia remains the dose-limiting toxic reaction. However, antitumor responses were observed at dosage levels which produced minimal platelet depression.R It is our contention in developing this agent that the principal potential for chlorozotocin lies in its use as a non-myelosuppressive component of combination chemotherapeutic regimens. Therefore, for Phase I1 studies we selected a dose of 120 mg/m2, which represents the maximum dose which did not cause thrombocytopenia, but did produce clinical remissions. Materials and MethodsThirty-five consecutive patients with metastatic melanoma were selected for this trial. The median age of the 21 men and 14 women as a whole was 55 years (range, 21 -76 ye...
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