[Therapy of acute nonlymphocytic leukemia: 2. Biological characteristics and prediction of response].
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Biomedical subjects
Publications and source records attributed to Y M Rustum.
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A method for continuous infusion of drugs into the tail vein of rats was developed. This simple procedure has the advantage of permitting freedom of movement of the animal during extended drug exposure. Utilization of an aluminum sheath as a tail cover prevents destruction of the cannulating apparatus without placing additional stress upon the animal. This method produced no adverse effects upon rats during prolonged infusion (up to 7 days) and may be useful in the routine evaluation of agents having a short plasma half-life. The lethality of FU alone or in combination with TdR was evaluated with this technique. Infusion of up to 10 gm/kg/72 hr of TdR produced no mortality. Co-administration of TdR at 1 gm/kg/72 hr with FU, however, potentiated the toxicity of FU. These data indicate that the toxicity of FU may be modified by provision of TdR with this method.
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Centrifugal elutriation was used to separate human acute leukemia cells into proliferative and quiescent subpopulations. Ten bone marrow specimens and 5 peripheral blood specimens were subjected to centrifugal elutriations. From each patient, leukemic cell subpopulations were obtained for which the [3H]thymidine labeling index differed by 10- to 30-fold. In 6 of the marrow specimens and in 2 of the peripheral blood specimens, cell subpopulations were obtained for which the labeling index exceeded 20%. In 5 marrow specimens, subpopulations were obtained for which the labeling index exceeded 40%. Preliminary studies of the uptake of 1-beta-D-arabinofuranosylcytosine and 5-azacytidine failed to show any correlation between drug uptake and the proliferative characteristics of the leukemic subpopulations.
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Phospholipid vesicles have been used as a carrier vehicle to enhance the cytotoxic activity of 1-beta-D-arabinofuranosyl-cytosine (ara-C) and 1-beta-D-arabinofuranosylcytosine 5'-triphosphate against several tumor cell lines. The activity of both compounds in free solution or entrapped within phospholipid vesicles was compared against L1210 cells, Ehrlich ascites cells, and SV40-transformed 3T3 cells in vitro. In addition, the activity of vesicle-entrapped ara-C against L1210 cells was also studied in vivo. The results obtained in vitro with ara-C indicated no difference in the concentration needed to inhibit growth of cells by 50% between free ara-C and vesicle-entrapped ara-C. In contrast, 1-beta-D-arabinofuranosylcytosine 5'-triphosphate entrapped in phospholipid vesicles was a more potent inhibitor of L1210 in culture (ID50, 2 X 10(-8) M) compared to the relatively inactive free 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (id50 greater than 10(-7) M). Experiments carried out with L1210 cells in mice showed that, after a single i.p. dose (10 mg/kg) of vesicle-entrapped ara-C, the average survival times of mice inoculated with 10(5) L1210 cells were increased by over 90%. In control experiments, free ara-C or vesicles plus free ara-C (10 mg/kg) did not prolong survival of mice.
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