Masao Oguro

(2″-R)-4′-o-Tetrahydropyranyladriamycin, a new anthracycline derivative; its effectiveness in lymphoid malignancies

SummaryThirty-eight patients with adult acute lymphoblastic leukemia (ALL) or non-Hodgkins lymphoma (NHL) were treated intravenously with (2″-R)-4′-o-Tetrahydropyranyladriamycin (THP) at a dose of 10 mg/m2 for 5 consecutive days. Seven complete and 15 partial responses were observed in 35 evaluable patients (overall response rate, 62.8%). Both antitumor activity and antitumor spectrum were similar to those for doxorubicin. Since the patients who had had chemotherapy previously, including other kinds of anthracycline, responded rather poorly to THP, cross-resistance between THP and other anthracyclines may be present. Leukopenia and thrombocytopenia were dose-limiting factors. Nausea and vomiting episodes were mild, and epilation was also minimal. Although the observation period was short and a cumulative dose was not large enough to evaluate cardiotoxicity, there were no abnormal EKG changes or clinical signs of cardiotoxicity in this study. THP is a potent antitumor agent in the treatment of lymphoid malignancies.

4-Piperidinopiperidine-resistant lymphoma cells were resistant to dexamethasone- and A23187-induced apoptosis

4-Piperidinopiperidine is a side residue of CPT-11, a derivative of camptothecin. We have previously established a 4-piperidinopiperidine-resistant lymphoma cell line, 4-pp-R, which was co-resistant to CPT-11. We report here that this cell line is cross-resistant to dexamethasone and A23187 which induce apoptosis in parent RVC cells. Examination of apoptosis-related gene expression by RT-PCR showed that bcl-2 expression was greater in 4-pp-R than in RVC. p53, bax and bcl-xL were expressed at the same level in 4-pp-R and RVC cells. These results suggest that upregulation of bcl-2 in 4-pp-R cells is related to the resistance to CPT-11 as well as to A23187 or dexamethasone.

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 study of NKT-01

A phase I study of NKT-01 (deoxyspergualin), which is a derivative of an antitumor antibiotic, spergualin, was performed by a cooperative study group. NKT-01 was given intravenously by 3-h infusion. The effect of single administration was studied prior to evaluation of daily administration for 5 consecutive days. In all, 5 and 33 patients with various malignancies, including leukemia, were entered into the trials of single and daily administration, respectively. In the single-administration study, all patients were evaluable and no clear adverse effect was observed at doses ranging from 20 to 320 mg/m2. In the daily-administration study, 28 evaluable patients (16 men and 12 women; median age, 55.5 years) were treated with a daily dose of 20–500 mg/m2. Toxicities such as myelosuppression, mild nausea/vomiting, anorexia, alopecia, tongue and perioral numbness, and hypotension were observed dose-dependently during or after the treatment. Grade 2 leukopenia, thrombocytopenia, and anemia were experienced at a dose of 500 mg/m2. These usually recovered to normal values by approximately 3 weeks after treatment. A pharmacokinetic analysis of single administration revealed rapid plasma clearance, with mean half-lives for the α and β phases being 28 min and 6.9 h, respectively. Approximately 12% of the infused dose was excreted into the urine in unmetabolized form. The pharmacokinetic parameters obtained after 5-day administration were similar to those recorded after single administration. Concerning treatment response, a transient but significant reduction in the number of leukemic cells was observed in one patient with adult T-cell leukemia. In this study, perioral numbness, hypotension, and hematological toxicity were concluded to be dose-limiting, with the maximal acceptable dose being 500 mg/m2. The recommended dose for a phase II study of NKT-01 against solid tumors was judged to be 400 mg/m2 given daily by 3-h infusion for 5 days, every 3 weeks. In hematological malignancies, however, higher myelosuppressive schedules of administration should be investigated.

A lymphoma cell line resistant to 4-piperidinopiperidine was less sensitive to CPT-11

Abstract CPT-11 is a promising new anticancer drug in which 4-piperidinopiperidine is a side-chain structure. In the present studies, we examined the role played by 4-piperidinopiperidine in the pharmacological activity of CPT-11. When T-cell lymphoma RVC cells were incubated with 4-piperidinopiperidine at concentrations higher than 50 μg/ml, the cells underwent apoptosis with a nucleosomal ladder of chromosomal DNA on agarose gels in a dose-dependent manner. We then established a cell line resistant to 4-piperidinopiperidine (4-pp-R), which was about 20-fold more resistant to 4-piperidinopiperidine than the parent RVC cells. Moreover, 4-pp-R cells showed coresistance to CPT-11. However, the growth rate and cell cycle population of 4-pp-R cells were not different from those of the parent RVC cells, and there were no differences between the two cell lines with regard to their drug transport system, CPT-11-metabolizing activity, their activity and amount of topoisomerase I, or their sensitivity to either SN-38 or etoposide, suggesting that the cytotoxicity of CPT-11 is not a consequence of the activity of its metabolite SN-38. The present studies suggested that resistance to CPT-11 is in part due to insensitivity to 4-piperidinopiperidine and its metabolites, since 4-piperidinopiperidine was cytotoxic and 4-pp-R cells were less sensitive to CPT-11.

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.

Phase II study of NK313 in malignant lymphomas: an NK313 Malignant Lymphoma Study Group trial

SummaryLiblomycin (NK313) is a bleomycin analog that has proved to be associated with less pulmonary toxicity and with more potent antitumor activity than bleomycin in animal tumors. In a phase I study, pulmonary toxicity was not observed, whereas myelosuppression was the dose-limiting factor. The maximum tolerated dose was 140 mg/m2 given once a week for 4 weeks. In the present phase II study, patients with malignant lymphomas received liblomycin at 80 or 100 mg/m2 by intravenous infusion over 15 min once a week for 4 weeks. A total of 39 patients were entered, and 31 [4 with Hodgkins disease (HD) and 27 with non-Hodgkins lymphoma (NHL)] were evaluable. The median age of the patients was 52 years (range, 22–74 years), and their performance status ranged from 0 to 3. In all, 28 of the patients had a history of intensive anticancer chemotherapy. Responses were evaluated according to WHO criteria. We obtained 1 complete remission and 9 partial remissions (PRs), for an overall response rate of 37%, in the 27 patients with NHL, whereas 1 PR was achieved in the 4 patients with HD. In all, 9 PRs (32.1%) were obtained in patients who has been exposed to prior chemotherapy, including 4 PRs (33.3%) in 12 patients who had previously been treated with bleomycin. Myelosuppression and nausea and vomting were the major toxicities, which occurred in about 50% of the patients, and myelosuppression was severe in two patients treated at a dose of 100 mg/m2. We concluded that liblomycin demonstrated significant antitumor activity against malignant lymphomas.

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.