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The objectives of this study were to determine the toxicity of intratumoural/intrapleural SRL172 in addition to intradermal SRL172 and standard chemotherapy (mitomycin-C, vinblastine and cisplatin) in patients with malignant mesothelioma. Patients received chemotherapy (mitomycin-C: 8 mg m−2, vinblastine: 6 mg m−2, cisplatin 50 mg m−2) on a 3-weekly basis for up to six courses. IP SRL172 injections were given 3-weekly prior to chemotherapy and escalated in groups of three patients from 1 μg to 1 mg bacilli in 10-fold increments. Patients were also given ID SRL172 at a dose of 1 mg bacilli 4-weekly. Patients were assessed for toxicity after each course of chemotherapy and for response by CT imaging. Immuno-haematological parameters were analyzed pre-treatment and 1 month after completion of treatment. There was no dose limiting toxicity with IP SRL172 although there was greater toxicity at the highest dose (n=13). There were six out of 16 partial responses (37.5%). Haemato-immunological parameters, measured in seven patients pre and post-therapy, revealed that response rate correlated with a decrease in platelet count and there was an increase in activation of natural killer cells and a decrease in the percentage of IL-4 producing T cells in all tested patients post-treatment. SRL172 can be given safely into tumour deposits and the pleural cavity in patients with malignant mesothelioma and we have established the dose for phase II testing. British Journal of Cancer (2002) 86, 336–341. DOI: 10.1038/sj/bjc/6600063 www.bjcancer.com © 2002 The Cancer Research Campaign

The effect of idoxifene, a novel anti-oestrogen with less agonist activity than tamoxifen, was compared with that of tamoxifen on the growth of hormone-dependent MCF-7 breast cancer xenografts. Forty tumours were established with oestradiol support in ovariectomized athymic mice, allowed to grow to a median volume of 420 mm3 and then continued with oestradiol, no support, tamoxifen or idoxifene delivered by 1.5-cm silastic capsule. Tumour regression occurred with both anti-oestrogens, although maximum regression was observed following oestradiol withdrawal alone. While prolonged anti-oestrogen therapy was associated with static growth, tumour volumes were significantly lower with idoxifene (P=0.01). After 6 months, 0/10 idoxifene-treated tumours developed acquired resistance compared with 3/10 tumours treated with tamoxifen. In separate experiments, 94 animals were treated initially with oestradiol, tamoxifen, idoxifene or placebo following implantation with 1-mm3 pieces of either wild-type (WT) or tamoxifen-resistant (TR) MCF-7 tumour. After 4 months, only 1/11 WT tumours became established with idoxifene compared with 4/11 with tamoxifen, 8/12 with oestradiol and 0/12 with placebo. Likewise, fewer TR tumours were supported by idoxifene (3/12) than by tamoxifen (8/12) or oestrogen (11/12). These data indicate that, compared with tamoxifen, idoxifene shows reduced growth support of MCF-7 xenografts and may share only partial cross-resistance. Furthermore, the development of acquired anti-oestrogen resistance may be reduced during long-term idoxifene therapy. The drug's reduced agonist activity may, in part, explain these observations and indicate a preferable biochemical profile for breast cancer treatment.

Fifteen post-menopausal patients with advanced breast cancer were treated with the LH-RH agonist leuprorelin (D-leu6-des-gly10-Gn-RH-ethylamide) given in a dosage of 7.5 mg as a monthly subcutaneous depot injection, to assess the clinical activity and endocrine response to treatment. None of the 15 patients showed an objective response to treatment, although four patients had stable disease for at least 6 months. No toxicity was demonstrated. Endocrine effects after 4 weeks' treatment were as follows: mean levels of serum gonadotrophins fell to 10% of their pretreatment values; there were no significant changes in the levels of prolactin on treatment; there was a significant decrease in the levels of serum testosterone in 12 out of 14 patients; there were no significant changes in the levels of oestradiol, androstenedione and oestrone. The lowering of serum testosterone suggests that androgens in post-menopausal women may be partly produced by the ovaries, stimulated by LH and FSH. This fall in testosterone may explain why some post-menopausal breast cancer patients in other studies have been reported to respond to treatment with LH-RH agonists, as it would decrease the substrate for the peripheral synthesis of oestrogens.

Summary The use of the epipodophyllotoxin VP 16-213 is described in twenty patients with acute myelogenous leukaemia resistant to other chemotherapy. The drug was usually given in 5-day courses of 50 mg/m2 daily and occasionally in 24-hr infusions of 250 mg/m2, on the basis of its phase-activity. Complete remission was achieved in only two patients: in one of these, remission was maintained with VP 16-213 for 8 months, and in the other for 10 weeks. A partial response was achieved in one other patient. Seventeen patients showed no response. No responses or remissions were achieved when the drug was used in a 24-hr infusion. Side effects were minimal, and the degree of marrow depression much less than for most other agents known to be active in acute myelogenous leukaemia. It was of interest that remission was achieved in one patient without the customary period of marrow hypoplasia. It is suggested that, although VP 16-213 appears to have minimal activity in the dosage used here, improvement might be sought by increasing the dosage, by scheduling the drug in a different way, or by using it in a combination chemotherapy regime.