Implantation of tumor cells in the bladder following transurethral resection of superficial bladder tumors is believed to be one factor in the etiology of bladder tumor recurrences. Using an in vitro model system we have studied the initial interaction between bladder carcinoma cells and a naturally produced basement membrane-like substrate. Minced explants of superficial low grade human bladder tumors from 10 patients were plated into culture dishes coated with a naturally produced extracellular matrix (ECM). This ECM has been shown to resemble the human urothelial basement membrane and submucosa in its macromolecular composition and ultrastructural appearance. It was found that a firm attachment of the human bladder tumor cells occurred within one hour, reached a maximal value within 24 hours and was followed by flattening and proliferation of the plated cells. These results indicate that prevention of tumor implantation should be initiated in the first hour after transurethral resection of the bladder tumors. This assay can be used for the investigation of various treatments to prevent tumor implantation.

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Thirty-eight patients with stage III ovarian carcinoma were treated with a protocol consisting of an initial phase of induction of remission with cyclophosphamide, hexamethylmelamine, doxorubicin, and cisplatin (CHAD) combination chemotherapy and a second laparotomy for resection of residual tumors, followed by a consolidation phase with curative doses of whole abdominal radiation. Six patients (16%) had stage IIIA disease, ten (26%) IIIB, and 22 (58%) had stage IIIC disease. All patients received three to 14 courses of CHAD chemotherapy with a clinical response rate (complete [CR] and partial [PR]) of 91%. Thirty-three patients underwent the second operation. In 14 patients no residual tumor was found, and in another 11 residual tumors found were totally resected. Thus, 25 of 33 (76%) were classified as in pathological complete remission (PCR) after this operation. Whole abdominal irradiation was well tolerated, although 12 of 29 (42%) of the irradiated patients required more than a 2-week interruption of the treatment course because of leukopenia and/or thrombocytopenia. The actuarial 5-year survival and disease-free survival rates for the whole group were 27% and 17%, respectively, and for the 29 patients who received the complete sequence of the prescribed protocol treatments, 35% and 20%, respectively. A univariate analysis of clinical parameters showed that inherent biological features, such as histology and grade, were the most dominant factors affecting prognosis, and that neither the aggressive surgical approach employed, nor the high-dose whole abdominal irradiation, significantly affected the outcome. The long-term results suggest that although our combined modality protocol was well tolerated, it failed to enhance the cure of stage III ovarian carcinoma. The possible biological and therapeutic vectors affecting this outcome are discussed.

Aminotamoxifen was totally synthesized from p-nitrobenzoyl chloride via a Friedel-Crafts acylation. Then, by means of a Balz-Schiemann reaction, aminotamoxifen was converted into fluorotamoxifen. The triazene variation of this conversion, with a 25% yield, enables a rapid, one-step diazotization, incorporating a fluorine atom into the phenyl ring of the tamoxifen. This reaction may be useful for the preparation of low specific activity 18F-labeled tamoxifen, for distribution, and for estrogen-receptor studies. For these in vivo and in vitro studies, fluorotamoxifen was also synthesized from p-fluorobenzoyl chloride, and its chemical intermediates were compared with estradiol and hexestrol, for their receptor binding and competition, as well as for their uterotropic activity. It is demonstrated that tamoxifen and fluorotamoxifen are strong estradiol agonists and partial hexestrol agonists, while aminotamoxifen is a weak estradiol and hexestrol agonist.

A routine procedure has been developed for the establishment in culture of normal primary and secondary human mammary epithelial cells. The high (80-100%) rate of success resulted from the combined use of a serum-free medium supplemented with high-density lipoprotein (HDL) and of cell plating on a naturally produced extracellular matrix (ECM). Plating on ECM greatly improved cell attachment, plating efficiency and initial outgrowth. HDL supported epithelial cell proliferation and prevented their detachment and degeneration while the omission of serum prevented the growth of stromal fibroblasts. Under these conditions we obtained from each specimen, and regardless of the patient's age, pure and actively dividing epithelial cell cultures forming a tightly packed and non-overlapping cell monolayer covering the entire area of the culture dish. These epithelial cultures could be easily dissociated and subcultured at a split ratio of 1:10. The described procedure will promote studies on the role of hormones and growth factors in the proliferation and differentiation of human mammary epithelial cells and on the susceptibility of human breast epithelial cells to various transforming agents and anti-cancer treatments.