afimoxifene and Carcinoma--Ductal--Breast

Breast cancer prevention with pharmacologic agents requires that the breast be exposed to an effective drug; systemic exposure is unnecessary, and its harms lead many eligible women to decline preventive therapy. Local transdermal therapy (LTT) to the breast involves the application of active drugs to the breast skin, resulting in high concentrations in the breast but low systemic exposure. It is non-invasive, self-delivered, and not dependent on hepatic metabolism. Existing data on LTT include investigations demonstrating relief of mastalgia with topical 4-hydroxytamoxifen (4-OHT, an active tamoxifen metabolite). Two presurgical window trials in women with invasive breast cancer, and ductal carcinoma in situ (DCIS) demonstrate that LTT decreases proliferation of invasive and non-invasive cancer cells to a similar degree as oral tamoxifen, with low systemic levels, and no effect on coagulation proteins. These data are promising regarding the use of LTT for the primary prevention of breast cancer, and for therapy of DCIS, since systemic exposure is not required for either of these purposes. They also suggest that an LTT approach could be developed for any small, lipophilic molecule with good dermal permeation, thus greatly expanding the menu of drugs that could be tested for breast cancer prevention.

Topics: Administration, Cutaneous; Animals; Anticarcinogenic Agents; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Chemoprevention; Cyclooxygenase 2 Inhibitors; Female; Gels; Humans; Mastodynia; Nanoparticles; Permeability; Receptors, Progesterone; Retinoids; Skin; Skin Absorption; Tamoxifen

Patients with estrogen receptor (ER)-positive breast cancers have a better prognosis than those with ER-negative breast cancers, but often have low sensitivity to chemotherapy and a limited survival benefit. We have previously shown a combination effect of taxanes and fulvestrant and suggested that this treatment may be useful for ER-positive breast cancer. In this study, we evaluated the effects of combinations of hormone drugs and chemotherapeutic agents. In vitro, the effects of combinations of five chemotherapeutic agents (doxorubicin, paclitaxel, docetaxel, vinorelbine, and 5-fluorouracil) and three hormone drugs (fulvestrant, tamoxifen, and 4-hydroxytamoxifen) were examined in ER-positive breast cancer cell lines using CalcuSyn software. Changes in chemoresistant factors such as Bcl2, multidrug resistance-associated protein 1, and microtubule-associated protein tau were also examined after exposure of the cells to hormone drugs. In vivo, tumor sizes in mice were evaluated after treatment with docetaxel or doxorubicin alone, fulvestrant alone, and combinations of these agents. Combination treatment with fulvestrant and all five chemotherapeutic agents in vitro showed synergistic effects. In contrast, tamoxifen showed an antagonistic effect with all the chemotherapeutic agents. 4-Hydroxytamoxifen showed an antagonistic effect with doxorubicin and 5-fluorouracil, but a synergistic effect with taxanes and vinorelbine. Regarding chemoresistant factors, Bcl2 and microtubule-associated protein tau were downregulated by fulvestrant. In vivo, a combination of fulvestrant and docetaxel had a synergistic effect on tumor growth, but fulvestrant and doxorubicin did not show this effect. In conclusion, fulvestrant showed good compatibility with all the evaluated chemotherapeutic agents, and especially with docetaxel, in vitro and in vivo.

Topics: Animals; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Ductal, Breast; Docetaxel; Doxorubicin; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Estradiol; Estrogen Receptor Modulators; Estrogens; Female; Fluorouracil; Fulvestrant; Humans; Mice; Mice, Nude; Neoplasm Proteins; Neoplasms, Hormone-Dependent; Paclitaxel; Random Allocation; Tamoxifen; Taxoids; Tumor Cells, Cultured; Vinblastine; Vinorelbine; Xenograft Model Antitumor Assays

The effects of estradiol, medroxyprogesterone acetate (MPA) dexamethasone, dihydrotestosterone and the antihormones 4-OH tamoxifen and RU 38486 were studied in two established breast carcinoma cell lines, the estrogen-sensitive ZR-75-1 and the estrogen-independent BT 20 cells applying two different in vitro systems, spheroid and monolayer cell culture in steroid deprived medium. Growth of ZR-75-1 spheroids was dramatically stimulated by the addition of estradiol, an effect which was neutralized by the simultaneous addition of 4-OH tamoxifen. The antiestrogen alone as well as dihydrotestosterone and MPA reduced ZR-75-1 spheroid growth significantly. While growth of BT 20 spheroids was only transiently inhibited by tamoxifen and dihydrotestosterone, a persistent increase in BT 20 spheroid growth was observed under MPA treatment in a concentration of 1 microM. This effect, although statistically significant, was very moderate. With the exception of this finding, growth effects of the different test compounds were similar in both in vitro systems, tumor spheroids and monolayer cell cultures.

Topics: Breast Neoplasms; Carcinoma, Ductal, Breast; Cell Division; Dexamethasone; Dihydrotestosterone; Estradiol; Estrogen Antagonists; Humans; Medroxyprogesterone Acetate; Mifepristone; Spheroids, Cellular; Steroids; Tamoxifen; Tumor Cells, Cultured