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THE Genito-Urinary Tract Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer (EORTC) has performed a series of phase II studies with strict criteria for the assessment of response in patients with bidimensionally measurable soft tissue or visceral metastases [ 1, 21. Reviewing chemotherapy in urological tumours, Stoter and Williams [3] concluded that methotrexate was not useful in the treatment of prostate cancer. Response to methotrexate in the American National Prostatic Cancer Project (NPCP) protocol 1100 was only 5% [4]. However, the scheduling of methotrexate doses was under investigation in the mid-1980s and in view of activity in other adenocarcinomas (e.g. breast cancer), together with anecdotal reports of activity in prostate cancer, a phase II study of ‘low-dose’ methotrexate (40 mg/m’) given every 2 weeks was started to investigate the effectiveness and toxicity of this schedule in prostate cancer patients. Entry criteria included: positive histology, bidimensionally measurable (clinical, ultrasound, computed tomography) soft tissue or visceral lesions to assess response, age 75 or less, additive hormone therapy to be stopped at least 1 day before the start of therapy, no previous chemotherapy or radiotherapy to the indicator lesion(s), WHO performance status 2 or better, life expectancy greater than 60 days, initial white blood count 3 X 109/1 or greater, initial platelet count 100 X 109/1 or greater, adequate renal function (serum creatinine 120 u,moYl or less, creatinine clearance greater than 75 ml/mm), adequate liver function (bilirubin less than 20 mmol/l), no second tumour, no significant cardiac disease, and no uncontrolled infections. Resnonse was assessed after every two cvcles. WHO criteria for evaluation of response and toxicity were-used [5]. 28 patients with documented progressive hormone-resistant disease entered the study between January 1986 and April 1989. 4 patients were ineligible; 1 had no measurable lesion and 3 had not received previous hormone therapy as required by the protocol. Of the 24 eligible patients (age 46-75 years, median 63.5 years), all had received previous androgen suppressive therapy; in addition 2 had received estramustine phosphate and eight had received radiotherapy to various sites. WHO performance scores were: 0 in 4 patients, 1 in 14, and 2 in 6. 1 natient died before the first assessment after two cvcles (early death from malignant disease). 1 patient died of toxicity after one cycle (early death from toxicity) with nausea and vomiting WHO grade 3, diarrhoea grade 4, oral toxicity grade 4, liver toxicity grade 1, renal toxicity grade 1 and minor haemorrhage. A toxic death was also reported in 1 patient who had a further cycle of therapy after withdrawing because of progression. No complete responses were observed. One patient (5%) had a partial response in inguinal lymph nodes, 10 patients (46%) showed no change and 11 patients (50%) had progressive disease. Full doses of drug were given with all cycles of treatment. Leucovorin rescue was only given if toxicity was encountered. The median number of courses was two (mean 3.5, range l-10). The dose was delayed (3-7 days) on three occasions. Haematological toxicity was tolerable. The lowest white cell count was 3.2 x 109/1 (range 3.2-9.7 x 109/1, median 4.5 x 109). The lowest platelet count was 17 x 109/1 (range 17-530 X 109/1, median 174 X 109). Methotrexate at a dose of 40 mg/m2 given every 2 weeks (with

The cytotoxic effect of doxorubicin on human breast cancer cells (MCF- 7 ) appeared to be correlated with drug concentration, exposure time and cellular uptake of doxorubicin. The effects of short-term stimulation of the growth of MCF- 7 cells with 30 pM oestradiol was investigated with respect to the uptake of doxorubicin and cell kill. Culture of MCF- 7 cells in steroid hormone-deprived medium resulted in an approx. 90% arrest of the cells in the G0G 1 -phase of the cell cycle. Growth stimulation with 30 pM oestradiol caused a 3–5 -fold increase in the number of cells in S-G2M phase at between 18 and 24 h after administration of oestradiol to the medium. Incubation of oestradiol-stimulated cells with 0.37 μM doxorubicin during both 1 and 6 h resulted in an augmented inhibition of cell growth compared to unstimulated controls. An enhanced cellular uptake of doxorubicin after administration of oestradiol was observed only after an incubation period of 6 h and not of 1 h . These observations suggest that both an increased sensitivity to doxorubicin and an augmented cellular uptake of the drug may underlie the cytotoxic effects of doxorubicin after pretreatment with oestradiol.

Three patients with metastatic prostatic cancer were treated for 10, 6 and 2 months with the potent LHRH-agonist Buserelin (Hoe 766) as a first-line agent. All showed a fall of elevated prostatic acid phosphatase levels (nearly undetectable after treatment in 2 patients) parallel to plasma testosterone with a relief of complaints after 3–4 weeks of treatment. Two patients had an increment of appetite and body weight. In some patient radiological evidence for objective tumour regression was found by CT scan of the prostate (decrease of 41% in prostate volume), skeletal X-rays and bone scan. In this patient plasma alkaline phosphatase showed a transient increase parallel to disappearance of osteolytic bone lesions (indicating new bone formation) followed by a normalization. It is concluded that LHRH-agonist treatment is effective in patients with metastatic prostatic carcinoma in the absence of serious side-effects.