[Clinical studies of BH-AC-DMP in adult acute nonlymphocytic leukemia].
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Biomedical subjects
Publications and source records attributed to R Ohno.
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Ten patients with multiple myeloma were treated with human lymphoblastoid interferon (HLBI). The dosages used were 3 X 10(6) IU to 6 X 10(6) IU of HLBI intramuscularly daily. Out of eight evaluable patients, one partial remission and 3 minor response were observed. More than half patients experienced fever exceeding 38 degrees C and mild myelosuppression. Other toxic effects consisted of anorexia, malaise, liver dysfunction and skin rash. On the basis of our preliminary study, we conclude that HLBI is an effective agent against multiple myeloma.
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Two metabolites of N4-behenoyl-1-beta-D-arabinofuranosylcytosine (BH-AC) were found in the plasma and urine, and a hydrolytic product, arabinosylcytosine (ara-C) and its deaminated product, arabinosyluraci (ara-U), were found in a preclinical study using monkeys. Of a given dose, 96% was found as ara-U and 3% as ara-C in urine in 24 h. The plasma disappearance curve of BH-AC is biphasic; the half-life of the initial phase is 40 min and that of the second phase is 120 min. At 8 h the BH-AC level is 21.9 micrograms/ml and falls exponentially to 3.6 micrograms/ml by 12 h. Ara-C was detected at the levels of 0.4-0.6 microgram/ml for 4 h. Comparative data of pharmacokinetic parameters among BH-AC, ara-C, and O2,2'-cyclocytidine showed that BH-AC had the longest plasma half-life, the smallest elimination-rate constant and the smallest excretion-rate constant. The plasma-clearance study of BH-AC in 13 patients showed essentially a pattern similar to that in monkeys; the plasma t 1/2 of 60 min in the first phase and of 180 min in the second. The BH-AC level at 2 h is 15.4 micrograms/ml, and 1.8 microgram/ml at 8 h. Initial phase I study of BH-AC was evaluated in 14 patients with leukemia and other malignancies. The starting dose was 1.5 mg/kg given as a single IV infusion for 3. The doses were when escalated up to 5.0 mg/kg. No side effects were noted with a single dose schedule. Daily consecutive infusions of 2.0 mg/kg-6.0 mg/kg for 4-21 days resulted in two patients having nausea, two anorexia, and one developing skin eruptions. Significant hematologic effects were noted with the daily infusion. One patient with acute myeloblastic leukemia achieved complete remission with 5.0 mg/kg BH-AC given daily for 21 days. It pharmacologic features, minimal toxicity, and the capability of inducing complete remission in acute leukemia indicate that BH-AC undoubtedly deserves further prospective clinical trials.
The mixed lymphocyte-tumor cell reaction (MLTR) between peripheral lymphocytes and cryopreserved autochthonous leukemia cells was studied in 36 adult patients with acute leukemia after complete remission as a result of chemotherapy. In 20 patients the lymphocytes showed a significant blastogenic response to autochthonous leukemia cells. Eleven out of 18 patients with acute myeloblastic leukemia and 4 out of 5 with acute monocytic leukemia showed positive MLTR, whereas 5 out of 13 with acute lymphoblastic leukemia gave a positive reaction. Cryopreserved leukemia cells of the patients with not only positive but also negative MLTR were able to stimulate allogeneic lymphocytes, except in one case. The relationship between MLTR and the prognosis of leukemia was analyzed in 30 patients who were alive more than 6 months after diagnosis. No apparent correlation was observed between MLTR and the survival time from diagnosis.
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In whole blood culture, pokeweed mitogen (PWM) is unable to stimulate human lymphocytes. This is because the mitogenic property of PWM is inactivated by erythrocytes, presumably due to absorption. The inactivation was observed with as few as 5 x 10(6)/ml of human erythrocytes. Therefore, when PWM is used to study the functions of human lymphocytes, especially of suppressor T lymphocytes, erythrocytes should be removed from lymphocyte preparations for accurate analysis.
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