Biomedical subjects
Publications and source records attributed to I Könyves.
This review presents the most important hormonal, cytotoxic and pharmacokinetic properties of estramustine phosphate. Furthermore the results of randomized Phase III trials are described in patients with hormone refractory prostatic cancer with and without previous irradiation. Several randomized studies are reported with Estracyt also in the primary treatment of this disease.
The efficacy of chemotherapy for prostatic cancer is difficult to evaluate owing to the low incidence of measurable indicator lesions and the resulting need for indirect response criteria. Although complete regressions remain exceptional, a number of agents, eg, doxorubicin and cisplatin have been shown to be effective in the treatment of this disease. So far, combinations of effective agents with or without concomitant hormone therapy have not proven to be more effective than single agents. Androgen priming has considerable theoretical appeal and deserves further consideration. A higher effectiveness of chemotherapeutic agents might be obtained by linkage to various carriers. Estramustine phosphate is an example of such a complex that has a cytotoxic effect in test systems in which estrogen has no effect and in patients with hormone-refractory prostatic cancer. The use of hormonal and other carriers that could increase the specificity of chemotherapeutic agents deserves extensive exploration.
The Scandinavian countries, especially Sweden and Norway, have a high incidence of prostate cancer. The tumor classification has been mainly uniform in recent years, according to the TNM system. Transrectal fine-needle biopsy and cytologic malignancy grading were introduced in Sweden and were gradually accepted in other countries. The treatment of prostate cancer has been mainly conservative as it is in most parts of Europe. For a long period endocrine therapy was given in the vast majority of cases. In recent years radiotherapy has also been used in cancer of low differentiation with no evidence of dissemination. In poorly differentiated and disseminated disease, Estracyt is the standard therapy. Estracyt is also given in disseminated carcinoma nonresponsive to ordinary hormone therapy. In this category of patients other chemotherapy is the second therapeutic alternative. Various techniques of endocrine therapy, chemotherapy, and radical surgery are subject to controlled trials.
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Antitumour agents in which various steroids were used as carriers for different cytostatic groups have been synthesized at the Research Laboratories of AB Leo, Helsingborg, Sweden. The chemical and pharmacological properties of two of these agents, estramustine phosphate and prednimustine, are reported. These agents have been shown to have good effects in the treatment of advanced hormone-resistant cancer.
In 23 patients with acute myeloid leukaemia (AML) and over the age of 64, four remissions (17%) were obtained with Prednimustine as a single drug. The daily dose was 24--60 mg orally. In 14 patients aged between 35 and 64 years who were treated with Prednimustine 60--80 mg daily and vincristine 2.25 mg i.v. every 7--10 days, six remissions were obtained (43%). Upon remission, patients were given ,0--40 mg of Prednimustine daily as maintenance therapy. Drug-induced pancytopenia preceding remission was not recorded in any patient. There were no side effects of major importance during maintenance therapy, and the median duration of remission was 8 months. It is concluded that the low toxicity of Prednimustine in normal bone marrow cells is of value, especially in elderly patients with AML.
Thirty-six patients with advanced ovarian carcinoma, 21 who had not responded to conventional surgery and irradiation therapy and 15 who had not responded to conventional surgery, irradiation therapy, and chemotherapy, were treated in a phase II study with Leo 1031. Objective responses were obtained in ten (28%) of the 36 patients (two complete and eight partial responses). An additional 11 (32%) patients had stable disease. The two complete responders were in remission for 4 months. During remission, all of the patients had an improved quality of life. Myelosuppression of varying severity occurred in 11 patients; three of these patients died from their complications. Two patients developed reversible confusion and one patient became psychotic. Eight patients became euphoric during treatment. Leo 1031 might be worthwhile as a palliative chemotherapy for patients with advanced ovarian carcinoma, but the risk of euphoria must always be considered since it can lead to voluntary overdosage.
The effect of Prednimustine was evaluated in 37 patients with generalised non-Hodgkin's lymphomas. The patients were divided into three groups according to dosage and previous treatment. Totally, in all three groups, 22 complete and 10 partial remissions were observed. During follow-up, five of the complete responders and all partial responders have relapsed. Leucopenia and thrombocytopenia were induced in several patients, but were always moderate and reversible after withdrawal of the drug. In some patients with a history of peptic ulcer or diabetes mellitus, these conditions were aggravated.
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Estramustine phosphate, a nor nitrogen mustard derivative of estradiol 17-beta-phosphate, was introduced in the treatment of prostatic carcinoma in 1966. Until March 1975, 466 patients have been reported on this treatment in open clinical trials: 82% of the patients were in stage IV. In 402 patients, nonresponsive to previous estrogen therapy, signigicant improvement occurred in 55%. In 64 previously untreated patients there was a favourable response in 83%. Side-effects were mainly bone marrow suppression. liver disturbance, thrombophlebitis following intravenous injection, and gastrointestinal troubles, mainly following oral administration. A prospective, randomized study comparing oral estramustine phosphate and conventional estrogen therapy in carcinoma of the prostate is in progress.
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