Twenty-five patients with metastatic prostate cancer resistant to primary hormone therapy, received highdose intravenous diethylstilbestrol diphosphate (Stilphostrol [Miles Pharmb DES-P) in a Phase I1 study using established response criteria. Objective response rate was 17%. while 22% of the patients were subjectively improved. Moderate gastrointestinal toxicity was reported in 10 patients (40%). Thromboembolic complications were seen in 2 (8%). The role of highdose Stilphostrol in the treatment of hormone-resistant prostate cancer is limited.Cancer W457-460, 1985.HE TREATMENT of patients with metastatic prostate T cancer no longer responding to primary hormone therapy (bilateral orchiectomy or estrogen) is investigational at this time.' The therapeutic options in such patients include chemotherapy, high-dose hormones, chemohormonal therapy, and biologic response modifiers. Most of the published literature relates to Phase I1 studies of chemotherapy. We have previously reported our initial experience with combination chemohormonal therapy where we observed a high response rate (50% acid phosphatase response, 63% clinical improvement) with a combination of Adnamycin (doxorubicin) and diethylstilbestrol diphosphate (Stilphostrol [Miles Pharm] or DES-P) in a pilot study of 19 patients2 This combination is now being investigated in a Phase I11 study by the Eastern Cooperative Oncology Group (ECOG).Our pilot study utilized very high doses of DES-P ( 1 g/day intravenously (IV) X7 followed by 1 g IV twice weekly) as the hormonal component. It is well established that in combination therapy each of the individual drugs should have demonstrated activity when used as a single agent.3 There is, however, limited Phase I1 data for DES-P as a single agent in patients with advanced prostate cancer failing primary hormone therapy. A study of 10 patients treated for 10 to 673 days with DES-P reported
A patient with metastatic prostate cancer is described where treatment with Adriamycin (doxorubicin) and estramustine produced severe hypophosphatemia (serum phosphate level, 1.2 mg/dl), which was reversible when treatment was discontinued. Previous studies have shown no effect of Adriamycin on serum phosphate levels. A retrospective study of serial serimm chemistry values was done in 15 patients treated with estramustine. A significant fall in the serum phosphate level (mean, 0.8 f 0.3 mg/dl) was observed during the first 6 weeks of treatment. When compaired with similar patients treated with bilateral orchiectomy, estramustine-treated patients had lower levels of serum calcium, fractional excretion of calcium, serum phosphate, and renal tubular threshold for phosphate reabsorption (TmPO,/GFR). Qualitatively similar but quantitatively smaller effects were also seen in a group of patients treated with diethylstilbestrol (DES) in a dose of 1 to 3 mg daily. Estrainustine appears to have significant effects on bone mineral metabolism, particularly on renal phosphate handling resulting in significant hypophospha-temia. This is probably due to an estrogenic effect. Cancer 58:2208-2213, 1986. STRAMUSTINE PHOSPHATE IS AN ORAL AGENT used E in the treatment of prostate cancer.'-6 It is a conjugate of estradiol 17p and an alkylating agent (mechlor-methamine). The precise mode of action of the drug is not Estramustine has been reported to produce responses in 10% to 35% of patients with metastatic pros-tate cancer no longer responsive to conventional hormone treatment." Toxicity is similar both qualitatively and quantitatively to that of diethylstilbestrol (DES) and includes nausea and vomiting, gynecomastia, fluid retention, thrombo-phlebitis, and occasional elevation of liver function tests. It is believed that estramustine owes part of its therapeutic action and toxicity to a high-dose estrogen effect.' For the past several years, we have treated patients with advanced (Stage D) prostate cancer whose disease is resistant to conventional hormone treatment with estra-mustine, either alone or in combination with Adriamycin (doxorubicin). In one patient, severe hypophosphatemia developed that was reversed only with discontinuation of
The hypothesis that biologic aggressiveness of bladder cancer is determined by carcinogen dose was tested using heterotopically transplanted rat urinary bladders (HTBs). Young male Fischer rats, which were recipients of normal bladders, were divided into three groups; the first group received 0.5 mg of N-methyl-N-nitrosourea (MNU) into HTBs for six doses, a second, 0.05 mg for six doses and the third, 1 mg for three doses. Separately, a group of animals received bladders from rats treated with 0.05% N-butyl-N-(4-hydroxybuty1)nitrosamine (BHBN) in drinking water for 4 weeks; the transplanted bladders then were treated with 0.5 mg of MNU for six doses. Treatment with the larger dose of MNU resulted in a significant increase in tumor incidence and frequency of invasive carcinomas. The combination carcinogen treatment induced more invasive carcinomas than the single treatment. The data suggest that deeply invasive carcinomas may develop in two ways: the first is by emergence of a more anaplastic cell population within a pre-existing noninvasive carcinoma and the second is by the de now development of an invasive carcinoma directly from a severely dysplastic urothelium, which is acceptable as carcinoma in situ. Squamous differentiation was characteristic of deeply invasive carcinomas. The dose of carcinogen(s) is a determinant of aggressiveness of bladder carcinomas. ARCINOMA OF THE URINARY TRACT is a spectrum C of neoplasms ranging from a low-grade superficial tumor to a deeply invasive tumor of high histologic grade, short duration, and rapid lethality.' A majority of them are of low-grade and characteristically "recur" following resection of a superficial tumor.The concept that there are at least two stages in the development of carcinoma, initiation and promotion, which originally was proposed for mouse skin carcinogenesis, has been shown to be applicable to the urothelial system as Typically, rat urothelium, after continuous exposure to a carcinogen, undergoes a series of changes before carcinoma develops; the earliest change is characterized by a generalized increase in epithelial cell layers (simple hyperplasia, [SH]). This is followed by loFrom the Departments of *Pathology and tUrology, Northwestern
N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN) has been considered to be a carcinogenic urinary metabolite of N-butyl-N-(4-hydroxybutyl)nitrosamine. No tumor developed, however, in the heterotropically transplanted rat urinary bladders (HTBs) following repeated instillation of BCPN dissolved in physiological saline. In the present study, the possibility that BCPN dissolved in urine may induce tumors was explored using a short-term screening assay. When tested with the concanavalin A agglutination assay with which a close correlation between increase in cell agglutinability and carcinogenicity of test compounds has been well demonstrated, no significant increase in agglutinability attributable solely to BCPN was observed in HTB cells whether it was dissolved in saline or urine. Based on the current findings together with other available data, it is suggested that urothelial cells have a very limited capability to activate BCPN to the ultimate carcinogen, and require continuous contact with the carcinogen to respond with tumor formation.
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