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Purpose: Patients with progressive or recurrent supratentorial high-grade gliomas were entered into a multicentre phase II trial to evaluate the efficacy and toxicity of temozolomide., Methods: The treatment schedule was 150-200 mg/m2 per day orally for 5 days repeated every 28 days. Response evaluation was by a combination of neurological status evaluation (MRC scale) and imaging., Results: Of 103 eligible patients enrolled, 11 (11%) achieved an objective response and a further 48 (47%) had stable disease. The median response duration was 4.6 months. Response rates were similar for anaplastic astrocytomas (grade III) and glioblastoma multiforme (grade IV) tumours. Predictable myelosuppression was the major toxicity., Conclusions: The observation of objective responses and tolerable side effects in this heterogeneous population of patients supports the further investigation of this agent in high-grade gliomas.

The purpose of the present study was to examine the effect of O6-benzylguanine (O6-BG) on the antitumour activity and toxicity of 8-carbamoyl-3-methylimidazo [5, 1-d]-1,2,3,5-tetrazine-4(3H)-one (temozolomide) in a human malignant melanoma xenograft model following single and multiple administration of the combination. O6-BG irreversibly inactivates the DNA-repair protein O6-alkylguanine-DNA alkyltransferase (AGT), which confers resistance to temozolomide. Preadministration of O6-BG (35 mg/kg, i.p.) 1 h prior to temozolomide (i.p.) was examined using single and daily x5 dosing regimens in athymic mice bearing subcutaneous A375P xenografts. The AGT activity of A375P tumors was 95 +/- 8 fmol/mg protein (mean +/- SE, n = 4). O6-BG alone completely suppressed xenograft AGT activity within 1 h of administration but had no effect upon tumor growth. O6-BG did not significantly increase the tumor growth delay induced by a single 200-mg/ kg dose of temozolomide (P > 0.05, two-tailed Mann-Whitney test) but did increase the associated mean body weight loss (P < 0.025). In contrast, when the same dose of temozolomide was divided into five equal fractions (40 mg/kg) and given with O6-BG on 5 consecutive days, a comparable increase in toxicity was accompanied by a very significant increase in tumor growth delay (P < 0.0025), equivalent to that produced by a 3-fold greater dose of temozolomide alone. O6-BG with temozolomide also produced a greater antitumour effect than an equitoxic dose of temozolomide alone on this schedule (P < 0.005). These data indicate that the enhancement of temozolomide antitumour activity by O6-BG preadministration is dependent upon the schedule of drug administration, with multiple dosing of O6-BG + temozolomide producing the greatest effect. The results also suggest that prolonged administration of the combination can lead to an increase in the therapeutic index of temozolomide.

A total of 50 consecutive adult patients with newly diagnosed aggressive non-Hodgkin's lymphoma were treated with a weekly alternating combination chemotherapy schedule, BEMOP/CA, including bleomycin, etoposide, methotrexate, vincristine, cyclophosphamide and Adriamycin. Two-thirds of the patients were over 60 years old or had stage 4 disease. Clinical remission was achieved in 56% of cases. The 3-year survival is 53% (95% confidence interval, 39-66%). The presence of B symptoms and a serum albumin value of <33 g/l at presentation were poor prognostic indicators for survival in a multivariate proportional-hazards model. Overall, the response rate and survival for this group of patients with intermediate- and high-grade lymphomas is similar to results previously reported. The BEMOP/CA treatment was brief (16 weeks) and associated with a low fatal toxicity (one early death and one late fatality from Pneumocystis pneumonia), and the drug costs are equivalent to those for eight cycles of CHOP.

Modulators of protein kinase C (PKC) were used to investigate the role of this enzyme during Adriamycin-induced erythroid differentiation of K562 cells. Adriamycin (0.1 microM) induced erythroid differentiation in 60% +/- 10% of K562 cells. Phorbol myristate-12-acetate, an activator of protein kinase C, was strongly anti-proliferative to K562 cells (IC50, 8 nM) but did not induce erythroid differentiation. Staurosporine inhibited PKC from K562 cells (IC50, 8 nM) and blocked Adriamycin-induced erythroid differentiation, but only at concentrations marginally below those that inhibited proliferation (IC50, 81 nM), 1-(5-Isoquinolinylsulphonyl)-2-methylpiperazine (H-7) inhibited K562 PKC (IC50, 26 microM) but reduced Adriamycin-induced differentiation by less than 50% at concentrations of up to 600 microM. These data argue against a major role for PKC during Adriamycin-induced erythroid differentiation in K562 cells.

A total of 24 patients who were receiving combination chemotherapy (POMB) including cisplatin at a dose of 100-120 mg/m2 were treated with the 5HT3 antagonist GR38032F (GR) as an anti-emetic prophylaxis. GR was given as a 15-min loading infusion followed by a 24-h infusion at three escalating dose levels of 1, 2 and 4 mg/h. In the first 24 h after commencing treatment, six patients had complete control of nausea and vomiting (CR), two had 1-2 emetic episodes (MR) and five had 3-5 emetic episodes (mR). The major response rate (CR + MR) was thus 35%. Eight responding patients (CR or MR) went on to receive oral GR at 8 or 12 mg t.i.d. for 5 days. In this group there was one CR, one MR, two mRs and four failures (F). There was no evidence of an improved therapeutic effect with increasing dose in either the infusion or the oral section of the study, although numbers were limited in the latter part of the trial. Toxicity was mild, with low-grade headache affecting 25% of patients being the most frequent side effect. Pharmacokinetic data was obtained in six patients at each dose level. There was a progressive rise in clearance with increasing dose, indicating that the kinetics are non-linear. However, there was no evidence of an association between high plasma levels and therapeutic efficacy. GR38032F is well tolerated and has promising single-agent activity in preventing vomiting induced by high-dose cisplatin.

Since 1976 we have used VP16-213 (Etoposide; NSC-141540) in several groups of patients with gestational choriocarcinoma. Initially we used VP16-213 in a dose of 100 mg/m2 by short i.v. infusion for 5 consecutive days in patients with drug-resistant gestational choriocarcinoma. Patients were monitored with twice weekly samples for serum human chorionic gonadotrophin (HCG) concentration and a partial response (PR) has been defined as a fall in the HCG concentration to less than one tenth and an improvement (IMP) as a fall in the HCG concentration to less than one half of the pre-treatment value. In gestational choriocarcinoma patients resistant to other drugs there were 7 (19%) PR, 14 (38%), IMP, and 16 (43%) of non-responders. Since 1979 we have used VP16-213 as the initial agent in patients in the medium risk category [1] and up to the 1st July 1981 we have treated 38 patients with VP16-213 in this group, There have been 13 (34%) PR and 17 (45%) IMP. There are currently 30 (79%) patients in complete remission. Six are still on treatment; only two required a change of treatment because of drug resistance and so far there has been only one relapse off treatment. We have also integrated VP16-213 in combination with methotrexate and actinomycin-D followed by vincristine and cyclophosphamide in the high risk category [1] and have so far treated 24 patients. There are 16 (67%) CR, four patients are still on treatment; only one patient failed to respond at all to therapy and there has been one relapse off treatment. There were three deaths in this high risk group. We think that VP16-213 should be regarded as one of the first line agents in treating patients with gestational choriocarcinoma who fall into the medium and high-risk categories.

Serum levels of etoposide obtained 5 min after administration of 100 mg/m2 were between 11 and 30 micrograms/ml. By 24 h after drug administration, serum levels had fallen to between 0.19 and 1.11 micrograms/ml. Interpatient variation of etoposide serum concentrations obtained 5 min after drug administration was low, whereas interpatient variation 24 h later was noticeably higher. A significant correlation was observed (r = -0.698) between the WBC nadir and the mean etoposide serum concentrations, measured 24 h after drug administration, in patients receiving etoposide in combination with cyclophosphamide and actinomycin D. However, a relationship was not observed in those patients receiving etoposide alone. There was no observed difference in the efficacy or toxicity of 500 mg/m2 etoposide when the dose was administered either as 100 mg/m2 on each of 5 consecutive days or as 250 mg/m2 on days 1 and 3. There was no significant difference between AUC values calculated from etoposide concentration versus time profiles in patients receiving the drug on days 1 and 3 and those values obtained with the 5-day schedule. Patients resistant to a conventional dose of etoposide were given a higher dose of 1 g/m2/24 h, but this schedule did not cause an increase in efficacy despite an increase in serum levels of the drug. CSF levels in two of these patients receiving high-dose etoposide were 1.28% and 2.09% of the serum concentrations.

Hypomagnesaemia is recognised as a feature of the renal tubular defect produced by cis-platinum therapy for cancer. It may be sufficiently severe to cause tetany and grand mal fits. Attempts to correct established hypomagnesaemia whilst continuing cis-platinum therapy have not proved satisfactory. We have therefore investigated the prophylactic addition of 3 g magnesium sulphate to the high-dose platinum regimen with which metastatic malignant teratoma is treated in this unit. Serum magnesium levels have been measured in eight patients treated in this way and compared with those recorded for eight matched patients previously treated without routine magnesium supplements. Magnesium levels fell into the range frequently associated with clinical manifestation in five of the eight unsupplemented patients and only one of those given magnesium prophylactically. Mean serum magnesium levels were significantly higher in the supplemented group when compared using the paired t-test (P less than 0.01). Routine supplementation with intravenous magnesium sulphate is a simple and effective way of preventing symptomatic hypomagnesaemia associated with cis-platinum therapy.

A total of 68 patients were treated in a phase I study of meta-azidopyrimethamine ethanesulphonate (MZPES)--a novel lipophilic dihydrofolate reductase (DHFR) antagonist. The dose was increased from 5.4 mg/m2 to 460 mg/m2 given as a 1-h infusion, with 460 mg/m2, 600 mg/m2 and 800 mg/m2 given as a 24-h infusion. The dose-limiting toxicity was nausea and vomiting, which was marked at doses above 360 mg/m2 by 1-h infusion and 600 mg/m2 by 24-h infusion. Above 250 mg/m2 patients also described subjective neurological symptoms, although no objective signs were apparent. Myelosuppression was not consistent at any dose level. No objective responses were seen. In view of the lack of anti-folate activity at toxic levels, no phase II trials are currently proposed; toxicological and in vitro studies will continue.

The in vivo antitumor activity of etoposide and mitozolomide was assessed in nude mice bearing a xenograft (CC3) of human gestational choriocarcinoma. Both agents demonstrated, at best, marginal activity observed as a delay in tumour growth. This lack of sensitivity suggests that the CC3 xenograft is not a good model for selection of agents for clinical evaluation in gestational choriocarcinoma. Plasma and tissue concentrations of etoposide and mitozolomide were measured in nude mice. Drug concentrations found in tumour tissue were 60% and 30% of plasma levels for mitozolomide and etoposide respectively. Etoposide and mitozolomide activity was also evaluated in vitro with another choriocarcinoma cell line (JAR). Maximum cell-kill was achieved after exposure to etoposide 0.05-1 microgram/ml for 3-24 h. In vitro response to etoposide demonstrates the importance of exposure time in determining cytotoxicity. In contrast, mitozolomide at concentrations from 1-100 micrograms/ml did not have a marked effect against JAR after exposure for 3-24 h.