Akira Hoshino

Treatment of acute myelogenous leukemia in adults with N4-behenoyl-1-β-D-arabinofuranosylcytosine

Forty‐five previously‐untreated adult patients with acute myelogenous leukemia (AML) were treated with N4‐behenoyl‐1‐β‐D‐arabinofuranosyl‐cytosine (BHAC) in a multi‐institutional cooperative study. Among 41 evaluable patients, 15 (36.6%) achieved complete remission (CR) and 10 (24.4%) achieved partial remission by daily administration of 3 to 8 mg/kg of BHAC. Higher daily doses (5 mg/kg or more) produced higher CR rates, and all of the CR were observed among the patients receiving a total BHAC dosage of 50 mg/kg or more in a period of 10 days or more. The side effects were mild and acceptable: nausea–anorexia was observed in 27% of the patients and vomiting in 17%. The results of this study thus indicate BHAC to be effective for remission induction of AML, and to deserve further clinical trials in combination with other anti‐leukemic drugs. Cancer 56: 1913‐1917, 1985.

Antitumor activity of MST-16, a novel derivative of bis(2,6-dioxopiperazine), in murine tumor models

SummaryWe studied the antitumor activity of newly synthesized bis(1-acyloxymethyl) derivatives of 4,4′-(1,2-ethanediyl)bis(2,6-piperazinedione) using i.p.-i.p. models of P388 leukemia and B16 melanoma. As a result, we found 4,4′-(1,2-ethanediyl)bis(1-isobutoxycarbonyloxymethyl-2,6-piperazinedione) (MST-16) to possess considerable therapeutic activity. MST-16 showed not only marked life-prolonging effects in both P388 leukemia- and B16 melanoma-bearing mice but also a greater therapeutic ratio than did its parent compounds, ICRF-154 and ICRF-159. Further studies revealed that MST-16 has considerable therapeutic activity against a number of other tumors such as ascitic forms of L1210 leukemia, colon 26 adenocarcinoma, and MH-134 hepatoma and solid forms of B16 melanoma, Lewis lung carcinoma, colon 38 adenocarcinoma, and M5076 fibrosarcoma. These results suggest that MST-16 is very promising as an antitumor agent.

Antitumor Effects of Adriamycin on Yoshida Rat Sarcoma and L 1210 Mouse Leukemia — Cross-resistance and Combination Chemotherapy

Adriamycin is a new antitumor antibiotic isolated from cultures of Streptomyces peucetius par. caesius [1]. The structural formula of adriamycin differs from daunomycin only in the substitution of a hydroxyl group for a hydrogen atom in the acetyl radical of the aglycone moiety of daunomycin [2]. Adriamycin was reported to possess a higher therapeutic index than daunomycin in serval experimental tumor systems [3, 4]. This paper deals with cross-resistance studies using various resistant sublines of Yoshida sarcoma in rats and L1210 leukemia in mice. Combination chemotherapy of adriamycin with various antitumor agents were also studied in L1210 leukemia.

Treatment of acute leukemia and malignant lymphoma with (2"R)-4'-O-tetrahydropyranyladriamycin.

SummaryEighty-four previously treated adult patients with acute leukemia and malignant lymphoma were treated with (2″R)-4′-O-tetrahydropyranyladriamycin (THP). THP (10–55 mg/m2) was administered by i.v. bolus injection daily for acute leukemia, and according to three different schedules for malignant lymphoma: daily, weekly or once every 3–4 weeks. Complete and partial remission (CR and PR) were achieved by 1 (5%) and 3 of 19 patients with acute myelogenous leukemia and by 2 (13%) and 3 of 15 patients with acute lymphoblastic leukemia, respectively. All CRs were in the groups receiving 25 mg/m2 THP daily. CR and PR were achieved by 6 (14%) and 8 of 42 patients with non-Hodgkin lymphoma (NHL) and by 4 (50%) and 2 of 8 patients with Hodgkins disease (HD), respectively. No particular sensitivity was found among the subtypes of NHL and HD. Response (CR+PR) was noted in 10 (40%) of 25 patients treated every 3–4 weeks, in 1 (17%) of 6 treated weekly, and in 9 (47%) of 19 treated daily. The major side effects were myelosuppression and gastrointestinal toxicities. Alopecia was observed in only 10 (12%) patients. ECG abnormalities were observed in 7 (10%) patients, all of whom had previously been treated with other anthracyclines. No severe cardiotoxicity was observed.

Phase I clinical and pharmacokinetic study of orally administeredN 4-palmitoyl-1-β-d-arabinofuranosylcytosine

A phase I study ofN4-palmitoyl-1-β-d-arabinofuranosylcytosine (PLAC) was conducted in 88 patients; 36 with solid tumors and 52 with hematological malignancies, using 2 different schedules. Schedule 1 employed a single oral administration and Schedule 2, 5-day consecutive daily oral administration. In Schedule 1, the daily dose was initiated with 1 mg kg−1 which was escalated up to 24 mg kg−1 according to the modified Fibonacci’s method. Side effects included nausea, vomiting and skin rashes, but myelosuppression was not seen within this dose range. In Schedule 2, the daily dose was started with 1 mg kg−1 which was escalated up to 24 mg kg−1. Major side effects were nausea, vomiting and amorexia, and mild myelosuppression was noted at 12 mg kg−1 or more. The dose-limiting toxicity was gastrointestinal toxicity, which appeared at 3.3 mg kg−1 or more and became frequent at 7 mg kg−1 or more. Pharmacokinetic study revealed that the plasma concentrations of PLAC and ara-C, obtained by the oral intake of 3.3 mg kg−1 or more of PLAC, were sufficient for these compounds to exert cytotoxic effects on various human leukemia cellsin vitro. Based on these observations and plausible mechanism of action of PLAC, further clinical study should be carried out in a treatment schedule of considerably prolonged administration period with 3.3–6 mg kg−1 day−1 of PLAC.

The effects of multiple combination chemotherapy with vincristine, cyclophosphamide (Endoxan), methotrexate, 5-fluorouracil, adriamycin and prednisolone (VEMFAH) for advanced breast cancer

SummaryThirty-eight patients with advanced breast cancer were treated with the ‘VEMFAH’ multiple-drug combination chemotherapy, consisting of vincristine (V), cyclophosphamide (Endoxan; E), methotrexate (M), 5-fluorouracil was evaluated by the UICC criteria. Among the 35 evaluable cases, 4 complete responses (CR), 23 partial responses (PR), 2 cases of no change (NC), and 6 of progressive disease (PD) were observed. The response rate (CR+PR) was 77.1%. The median duration of response was 52 weeks (8–192 weeks) or 12 months. In 32 patients who received more than two courses of therapy the 50% survival time of responders was 27.0 months, which was significantly longer than the 10.3 months of nonresponders (P0.05). Except for 2 patients who developed myocardial damage, the therapy was never terminated because of side effects. Cumulative cardiotoxicity was not apparent in this study. This multiple-drug combination chemotherapy with ‘VEMFAH’ is concluded to be an effective treatment for advanced and disseminated breast cancer.

Phase I clinical and pharmacokinetic study ofN 4-behenoyl-1-β-d-arabinofuranosylcytosine

A phase I study ofN4-behenoyl-1-β-d-arabinofuranosylcytosine (BHAC) was conducted in 66 patients, 41 with solid tumors and 25 with hematological malignancies. The patients received either a 2-h single intravenous (i.v.) drip infusion (Schedule 1) or consecutive daily 2-h i.v. infusions (Schedule 2). In Schedule 1 the daily dose was initiated with 1.5 mg kg−1 which was escalated up to 7 mg kg−1. Side-effects were mild, and included nausea, vomiting, epilation, and hot flushes. Because of the presence of the solvent vehicle, HCO-60 and in consideration of the mechanism of action of BHAC, the dose escalation was stopped at 7 mg kg−1. In Schedule 2, the daily dose was started with 1.5 mg kg−1 which was escalated up to 8 mg kg−1 and given for 2–16 days. Myelosuppression was found to be dose-limiting toxicity. The maximum tolerated dose (MTD) in patients with non-hematological solid tumors was assumed to be 5 mg kg−1 daily × 5 days. The plasma disappearance curve of BHAC looked biphasic, and when 4 mg kg−1 of BHAC were administered the half-lives of the initial phase (t1/2α) and the second phase (t1/2β) were calculated as 0.798 and 5.76 h respectively. In Schedule 2 complete remission was observed in 5 out of 21 patients with acute leukemia, one partial remission in Hodgkin’s disease, and one 1-B response (Karnofsky) in thyroid papillary adenocarcinoma.