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We studied the effects of 5-fluorouracil (5-FU) and isoprinosine (ISO) on 15 patients with previously untreated metastatic colorectal carcinoma. The patients were treated in a limited Phase I, II protocol. All patients received a fixed ISO dose of 4 g orally on days 1 through 5 of each cycle. Each cycle was repeated every 35 days. The first seven patients were treated with an initial 5-FU dose of 7.5 mg/kg intravenously (IV) on days 1 through 5, which was escalated to 11.5 mg/kg IV after the first course and to 13 mg/kg IV after the second course. The next eight patients were treated with an initial 5-FU dose of 11.5 mg/kg IV on days 1 through 5, which was escalated to 13 mg/kg IV on days 1 through 5. No major responses (complete or partial) were documented. Median survival for all evaluable patients was 33 weeks. Toxicity was predominantly gastrointestinal and hematologic and was considered moderate. Our data suggest that 5-FU and ISO, at the doses used, were ineffectual in the treatment of metastatic colorectal carcinoma.

The in vitro effect of a calf thymus extract, thymostimulin (TP--1), on the E-rosette-forming capacity and on the PHA blastogenic response of peripheral blood lymphocytes was evaluated in 20 patients with untreated Hodgkin's disease. The mean percentage of lymphocytes forming E rosettes increased in patients from 44.2% to 57.5% (P less than 0.005). The mean PHA stimulation index rose with all three concentrations tested, but returned to the normal range only with the highest PHA concentration (60 mu/ml). An increase in the immune parameters was greatest in those patients who presented with decreased E-rosetting cells of total lymphocyte counts or whose disease was Stage III or IV or of mixed cellular histology.

The pharmacokinetics of vincristine (VCR) after an intravenous bolus dose of 2 mg were studied in patients with cancer with and without a concomitant treatment with the calcium-entry blocker nifedipine (NIF). VCR concentrations were determined by a sensitive radioimmunoassay. Pharmacokinetic data were analyzed by a nonlinear weighted least-square regression program (SAS-NLIN). A tri-exponential model fitted the raw data better than a bi-exponential model in five of 14 (35%) patients treated with VCR alone and in seven of 12 (58%) patients treated with VCR plus NIF (P = NS). The T1/2 alpha was shorter in NIF-treated patients, whereas the T1/2 gamma was longer in the NIF-treated group. The NIF-treated group showed an increase in the AUC O-infinity and AUC 1 to 96 hours, and a decrease in the AUC 0 to 1 hour. Total plasma clearance of VCR and 7-day urinary excretion of VCR was reduced in the NIF-treated patients. These data suggest that, when VCR is administered to NIF-treated patients with cancer, there is a decrease in VCR clearance from the body. Theoretically, a greater cytotoxicity may be anticipated.

A patient with leukemic reticuloendotheliosis ("hairy cell" leukemia) with sideroblastic anemia and an epinephrine-induced platelet-aggregation abnormality is presented. Immunologic membrane marker studies supported a B-lymphocyte origin of the hairy cells. It is hypothesized that a defect in the pluripotent marrow stem cell may be responsible for the hairy cell leukemia and for the intrinsic abnormalities in erythrocytes and platelets.

T-cell phenotypes, as defined by murine monoclonal antibodies, (OKT3, OKT4, OKT8, OKIa1), and phytohemagglutinin (PHA) reactivity, were evaluated in E-rosette forming cells (T-cells) from 10 untreated chronic myelocytic leukemia patients. The proportion of T4+ cells was lower in patients than in controls (41.6 versus 61.7%, P less than 0.02); whereas the proportion of T8+ cells was similar in patients and controls. The decrease in T4+ cells in CML resulted in a decrease in circulating T4+/T8+ ratio (P less than 0.02). The Ia1+ T-cells were increased in most CML (8 of 9) patients, while control subjects never displayed Ia1+ T-lymphocytes (P less than 0.01). The PHA reactivity of E-rosette forming lymphocytes was significantly impaired in CML patients with respect to controls (P less than 0.02). The presence of Ia antigen on T-cells was positively correlated with the T8+ cell phenotype (P less than 0.001) and inversely correlated with the T4+ (helper) cell phenotype (P less than 0.05). Furthermore, there was a trend towards an inverse correlation between the PHA response and the level of Ia1+ or T8+ cells, there is no correlation between PHA reactivity and T4+ phenotype. The results suggest that the T-lymphocyte population from untreated CML patients is intrinsically abnormal.