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PubMed2003

Dexamethasone and medroxyprogesterone acetate elevate Nm23-H1 metastasis suppressor gene expression in metastatic human breast carcinoma cells: new uses for old compounds.

PURPOSE: Long-term elevation of metastasis suppressor gene expression in micrometastases represents a novel therapeutic strategy for breast and other cancers. We searched for well-tolerated compounds that could elevate Nm23 metastasis suppressor expression in metastatic human breast cancer cell lines. EXPERIMENTAL DESIGN: MDA-MB-435 and MDA-MB-231 human breast carcinoma cells were treated with dexamethasone or medroxyprogesterone acetate (MPA) in cultures containing either charcoal-stripped serum or FCS. Aspects of nm23 expression and function were determined. RESULTS: Previous investigation of the nm23-H1 promoter suggested that glucocorticoids may contribute to the elevation of Nm23-H1 expression. Dexamethasone elevated Nm23-H1 and Nm23-H2 protein levels in two metastatic human breast carcinoma cell lines 2-3-fold over a 4-day time course when cultured in steroid-free culture medium, with high-dose inhibition, via a traditional transcriptional mechanism. Elevation of Nm23-H1 expression was not observed using FCS-containing culture medium, which contains endogenous levels of corticosteroids, limiting the potential in vivo use of dexamethasone. MPA was investigated as a glucocorticoid receptor agonist. MPA elevated breast carcinoma Nm23-H1 protein expression 3-fold over a 10 nM to 1 micro M dose range when cultured in steroid-free or FCS-containing medium, with a shorter time course. Elevation of Nm23-H1 expression in the presence of endogenous corticosteroids found in FCS involved a distinct, glucocorticoid receptor-dependent, posttranscriptional mechanism of action. MPA had no effect on proliferation in vitro but reduced the soft agar colonization of metastatic breast cancer cell lines by approximately 50%. CONCLUSIONS: MPA represents a first generation lead agent for the elevation of Nm23-H1 metastasis suppressor expression and the inhibition of metastatic colonization.

Agar↗

PubMed1992

[Estimation of medroxyprogesterone acetate against a human endometrial tumor constituted from the established Ishikawa cancer cells by a subrenal capsule assay].

In order to establish a sensitivity test system for the evaluation of anti-cancer hormonal agents, we tried a long-term subrenal capsule (SRC) assay, using nude mice with a transplanted solid tumor of endometrial cancer cells (Ishikawa's line). Unlike DNA-affecting agents, anti-cancer hormonal agents exert cytostatic effects rather than cytocidal effects, and their evaluation in a short period is considered to be inaccurate. Our test system is somewhat difficult in terms of technique, but it is useful since it can (1) evaluate the agents in the relatively short period of 28 days and (2) compare the cytostatic anti-tumor efficacy of two or more agents under the same conditions. The rate of successful tumor transplantation in nude mice in our system is very high, i.e., more than 90%. Although there are some points which need improvement, our system is considered to be useful as an assay system for the development of anti-cancer hormonal agents and other similar chemotherapeutic agents for cancers. When medroxyprogesterone acetate (MPA) was evaluated by means of this system, the administration period, as well as the dosage, was found to be important.

Animals↗

PubMedDate not supplied

The effect of oestrogens and medroxyprogesterone acetate on the uptake of cytotoxic drugs by MCF-7 breast cancer cells.

Previous studies have shown that human breast cancer cells (MCF-7) show an increased response to a number of cytotoxic drugs after 48 h pretreatment with medroxyprogesterone acetate (MPA). As there is evidence that MPA can influence membrane fluidity, we have examined the effect of pre-treatment with MPA on the uptake of methotrexate (MTX) and vincristine (VCR) by MCF-7 cells. The effect of pre-treatment with oestrogen on cytotoxic drug uptake was also examined. After 48 h pre-treatment with MPA (40 or 160 nmol/L), the uptake of MTX was significantly reduced by 14%-44%. Uptake of VCR was also reduced (10%-16%) after pre-treatment of cells with MPA but to a lesser degree than detected for MTX. Pre-treatment with ethinyloestradiol increased the uptake of MTX by up to 45% but enhanced uptake was only detected in cells after exposure to MTX for 1 h. While the results from this study show that oestrogens or MPA can alter the uptake of cytotoxic drugs by MCF-7 breast cancer cells, it is not clear how the MPA dependent decrease in drug uptake enhances the response of MCF-7 to such drugs previously reported.

Antineoplastic Agents↗

PubMed1992

[Effect of high-dose medroxyprogesterone acetate on coagulative and fibrinolytic factors in patients with gynecological cancers].

Medroxyprogesterone acetate (MPA), which is widely used clinically as an anticancer steroid preparation, is a very useful drug that seldom causes severe side effects such as bone marrow suppression, and can be dispensed at the outpatient clinic for an oral administration at home to the advantage of QOL. Recently however, there have been several reports suggesting its relationship with thrombosis. We measured t-PA, protein C, factor X, AT III, TAT, plasminogen, PIC, fibrinogen, and D-dimer in 11 patients with gynecologic malignancies who are treated with MPA (600 mg/day) and 11 controls. Then we examined the effects of the drug on blood coagulation and fibrinolytic activities. No changes in these parameters clearly suggested thrombogenesis in either group at this measurement or during the observation period (17 months at the maximum). The present study found no remarkable abnormalities in the blood coagulation and fibrinolytic activities. Thus, to avoid the use of MPA to patients at risk is considered to be the most important precaution for prevention of thrombosis.

Antithrombin III↗

PubMed1992

Antiproliferative effect of leuprorelin acetate, alone or combined with tamoxifen or medroxyprogesterone acetate, on human breast cancer cell lines.

We have investigated the antiproliferative action of leuprorelin acetate (TAP-144) on human breast cancer cells, cultured in medium supplemented with charcoal-treated fetal calf serum. The analogue had no effect on cell growth of oestrogen receptor-negative MDA-MB-231 cells. Although ineffective when used alone, TAP-144 inhibited in a dose-dependent fashion the oestradiol-induced cell growth in oestrogen receptor-positive and oestrogen-sensitive MCF-7, ZR-75-1 and CG-5 cells. TAP-144 did not modify the growth inhibitory activity of tamoxifen on CG-5 cells. A high concentration of TAP-144 (10(-6) M) seemed to increase the antioestrogenic effect of medroxyprogesterone acetate (MPA) (10(-7) M) in the same model. The data reported indicate that, in our culture conditions, TAP-144 has a direct antitumour effect on breast tumour cells. Our findings concerning the promotion of the antiproliferative effect of MPA merit further investigation.

Antineoplastic Agents↗

PubMed1991

Breast cancer and depot-medroxyprogesterone acetate: a multinational study. WHO Collaborative Study of Neoplasia and Steroid Contraceptives.

To determine whether the long-acting injectable progestational contraceptive DMPA, depot-medroxyprogesterone acetate, alters the risk of breast cancer in women, a hospital-based case-control study was conducted in five participating hospitals in Nairobi, Kenya, Mexico City, Mexico, Bangkok, Thailand (two hospitals), and Chiang Mai, Thailand. 869 women with newly diagnosed breast cancer who were young enough to have used DMPA for contraception, and 11,890 women of similar age who had been admitted to hospital for conditions unrelated to steroid contraceptive use, were interviewed to obtain information about previous use of steroid contraceptives and suspected risk factors for breast cancer. DMPA had been used by 12.5% of cases and 12.2% of controls. Relative risk (95% Cl) in women who had ever used DMPA was 1.21 (0.96, 1.52). Risk was increased within the first 4 years of initial exposure, mainly in women under 35 years. This observation did not seem to result from selective surveillance for breast cancer in DMPA users. Risk did not increase with duration of use, and was not increased in women who had started to use DMPA more than 5 years previously. These results provide reassurance that women who have used DMPA for a long time and who initiated use many years previously are not at increased risk of breast cancer.

Abortion, Induced↗

PubMed1991

[Effect of short-term administration of medroxyprogesterone acetate on side reactions of combination chemotherapy with ADR, VDS and CDDP in primary lung cancer].

The effect of short-term (10 days) Medroxyprogesterone acetate (MPA) administration on side reactions of combination chemotherapy with ADR, VDS and CDDP for primary lung cancer was studied by comparisons of MPA administration group (20 cases) with non administration group (30 cases). 1) Frequency of vomiting, duration of nausea and body weight loss were significantly improved in MPA administration Group (p less than 0.01). 2) Leukocyte and neutrophil counts in MPA administration group especially 7-10 days after of chemotherapy were maintained higher than these of non administration group (p less than 0.05). 3) Major side effects including thromboembolism in MPA administration group had not been observed. These results indicated that short-term MPA administration was relatively safe and effective in combination chemotherapy including CDDP.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1991

[The elevation of serum iron level with oral administration of medroxyprogesterone acetate (MPA) in patients with breast cancer].

The elevation of serum iron level was noted in six out of 45 patients with breast cancers who were treated by medroxyprogesterone acetate (MPA) in Kinki University Hospital. Those six patients were not found to be involved in hemolysis and liver dysfunction during the treatment. The level of serum iron was demonstrated 205-338 micrograms/dl in the blood after MPA treatment. This elevation of serum iron level was not related with another anti-cancer agents. There was no observed serious complication with high level of serum iron. This is the first report of the elevation of serum iron level following MPA therapy for the patients with breast cancers.

Aged↗

PubMed1991

[A controlled study with medroxyprogesterone acetate (MPA) alone or in combination with cyclophosphamide (CPA) in the treatment of advanced or recurrent breast cancer unresponsive to other therapies. Osaka Study Group for the Treatment of Breast Cancer].

Forty-eight patients with advanced or recurrent breast cancer unresponsive to other therapies were treated orally with medroxyprogesterone acetate (MPA) 1,200 mg/day alone (Group A: 28 patients) or in combination with cyclophosphamide (CPA) 100 mg/day (Group B: 20 patients). Either complete response (CR) or partial response (PR) was obtained in eight (28.6%) patients of Group A and PR in five (25.0%) of Group B. The median duration of the response was 5.3 months in Group A and 4.4 months in Group B. Despite the expected better result of the combined chemo-endocrine therapy for Group B, there were no statistical difference in usefulness between the two regimens. No severe adverse reactions were observed in this study. We conclude that MPA alone is useful for treatment of patients with advanced or recurrent breast cancer unresponsive to other therapies.

Adult↗

PubMed1991

Effect of depot medroxyprogesterone acetate on testis of albino rats: ultrastructural and biochemical studies.

Testis of male albino rats treated with depot medroxyprogesterone acetate DMPA, at the dose of 1 mg/animal/day for 60 days showed degenerative changes in the late spermatids. The changes were related with the mitochondrial sheath of the midpiece, including the plasma membrane enclosing the mitochondria and the mitochondrial cristae. Except lactate dehydrogenase and alkaline phosphatase, all the testicular marker enzymes, viz. beta-glucuronidase, hyaluronidase, sorbitol dehydrogenase and acid phosphatase registered a significant decrease. The ultrastructural and biochemical changes are correlated, as the cellular degeneration is responsible for decrease in the activity of the marker enzymes.

Animals↗

PubMed1991

Depot-medroxyprogesterone acetate (DMPA) and risk of endometrial cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives.

This is a report of results from a case-control study of the relationship of the long-acting progestational contraceptive, depot-medroxyprogesterone acetate (DMPA) to risk of endometrial carcinoma. Prior use of DMPA and information on known and suspected risk factors for endometrial cancer were ascertained in personal interviews with 122 women with histologically confirmed disease and 939 controls selected from 2 hospitals in Bangkok and 1 in Chiang Mai, Thailand. Based on 3 exposed cases and 84 exposed controls, the relative risk of endometrial cancer was estimated to be 0.21 (95% confidence interval = 0.06, 0.79) in women who had ever used DMPA (but who had not first used DMPA in the year prior to diagnosis). All 3 exposed cases had also received estrogens pre-menopausally. Exposure to such estrogens enhanced risk of endometrial cancer and reduced the apparent protective effect of DMPA. Although based on small numbers of exposed women, the protective effect of DMPA appeared to last for at least 8 years after cessation of use. The reduction in risk of endometrial cancer is at least as great for DMPA as for combined oral contraceptives.

Adult↗

PubMed1991

Depot-medroxyprogesterone acetate (DMPA) and risk of epithelial ovarian cancer. The WHO Collaborative Study of Neoplasia and Steroid Contraceptives.

The use of depot-medroxyprogesterone acetate (DMPA), a long-acting progestational contraceptive, in relation to risk of epithelial ovarian cancer was examined in a hospital-based case-control study conducted in Mexico and Thailand. Women with histologically confirmed epithelial ovarian cancer (n = 224) diagnosed between 1979 and 1988 were compared with hospital controls (n = 1,781) matched on age, hospital and year of interview. Overall, 9.8% of cases and 12.9% of controls had ever used DMPA. The relative-risk (RR) estimate in women who had ever used DMPA, controlling for the confounding effects of number of live births and oral contraceptive use, was 1.07 (95% CI 0.6, 1.8). No consistent patterns of increasing or decreasing risk were noted according to duration of use, time since first or most recent use or age at first use of DMPA. These results suggest that the risk of epithelial ovarian cancer is not altered by the use of DMPA.

Confounding Factors, Epidemiologic↗

PubMedDate not supplied

Effects of tamoxifen, medroxyprogesterone acetate and estradiol on tumor growth and oncogene expression in MCF-7 breast cancer cell line transplanted into nude mice.

The effects of three hormonal agents with a different mechanism of action (tamoxifen [TAM], medroxyprogesterone acetate [MPA] and estradiol [E2]) on tumor growth, differentiation and oncogene expression were evaluated using the estrogen-receptor positive human breast carcinoma cell line MCF-7 transplanted into nude mice. In MCF-7 tumors treated with E2, tumor incidence, mean weight of tumors, 3H-thymidine labelling index, differentiation antigen HMFGM (human milk-fat globule membrane) and ras p21, c-myc, neu oncogene products, the level was significantly increased. On the other hand MPA suppressed all of them. TAM increased the level of c-myc expression and HMFGM antigen, but suppressed the others. This evidence indicates that E2 induces both proliferation and differentiation of MCF-7 tumor cells. MPA suppresses both proliferation and differentiation, and TAM induces differentiation and suppresses proliferation.

Animals↗

PubMed1991

[Plasma lipoprotein fractions in high-dose medroxyprogesterone acetate therapy in metastatic breast cancer].

Metabolic disorders induced by synthetic gestagens have been discussed under the aspect of single endocrine parameters or the carbohydrate or lipid metabolism. In order to obtain more complex information a prospective study of 26 patients was performed, who were treated with 1,000 mg medroxyprogesterone acetate (MPA) per day over a period of 5 weeks as a second-line therapy of breast cancer. Before treatment and afterwards once a week the serum concentrations of MPA, androstenedione, DHEA-S, cortisol, prolactin, insulin, c-peptide, glucose, cholesterol, triglycerides, phospholipids and the lipoprotein fractions (VLDL, IDL, LDL, HDL) were analyzed. Besides the reduction of the androgens and changes in the glucose regulation significant effects on the lipoprotein metabolism were observed, leading to the conclusion that under high-dose gestagen therapy very complex interactions of the endocrine and metabolic system occur.

Antineoplastic Agents↗

PubMed1990

[A case of disseminated breast cancer successfully treated with medroxyprogesterone acetate].

We reported the successful treatment of disseminated breast cancer with medroxyprogesterone acetate (MPA). The patient was a 52-year-old female with brain and bone metastasis developed 1 year after surgery. The primary tumor was ER-positive, and she had been treated previously with adjuvant therapy consisting of UFT and tamoxifen. Brain metastasis was surgically removed, but the following combination chemotherapy (epirubicin and vindesine) failed to result in further improvement. Then MPA (1,200 mg/day) was administered as the second-line therapy. After 6 months, multiple bone lesions showed remarkable calcification (PR) and disappeared completely (CR) 13 months later. But the patient was forced to discontinue MPA because of uncontrollable hyperglycemia. At this writing, CR was still being continued and the patient was enjoying favorable quality of life without any treatment. We confirmed that MPA was effective as the second-line treatment for disseminated breast cancer.

Adenocarcinoma↗

PubMed1990

[Effect of medroxyprogesterone acetate on the cell kinetics in primary breast cancer].

Effect of medroxyprogesterone acetate (MPA) on the breast cancer cell kinetics was investigated by flow cytometry on paraffin-embedded tissues. Nuclear DNA contents were measured in 67 primary cases. MPA, 1,2000 mg/day, was administered orally for two weeks in 12 cases (MPA group) and the remaining cases (n-MPA group) served as the controls, until the day before operation. The DNA histograms were compared between both groups. The mean percentage of G0 + G1 phase was higher and that of S-phase and G2 + M phase, lower, in the MPA group than those in the n-MPA group. Especially in estrogen receptor positive and premenopausal cases, a significant difference was present between both groups. These results suggest that MPA could inhibit DNA synthesis with a delay of the cell cycle progression in human breast cancer.

Antineoplastic Agents↗

PubMed1990

A randomized study on hormone-resistant prostatic cancer: estramustine phosphate versus low dose epirubicin with or without medroxyprogesterone acetate. A Norwegian multicenter study.

A prospective randomized study has been carried out in order to compare three different treatment modalities for symptomatic metastatic hormone-resistant prostatic cancer. A total of 79 patients were included. One group was treated with estramustine phosphate, another with Epirubicin plus Medroxyprogesterone acetate (MPA), while the third arm consisted of Epirubicin plus placebo. Best palliation was obtained by the combination of Epirubicin and MPA. This combination also seemed to be associated with the longest response duration.

Administration, Oral↗

PubMed1990

Effect of tamoxifen and high-dose medroxyprogesterone acetate (MPA) on cell-mediated immune functions in breast cancer patients.

In 48 postmenopausal patients with non-disseminated breast cancer an adjuvant therapy with tamoxifen, and in 17 breast cancer patients with disseminated disease a therapy with high-dose medroxyprogesterone acetate (MPA) was performed and the results obtained were compared to a control group of 35 postmenopausal patients with non-disseminated disease receiving no further adjuvant treatment and 9 patients with disseminated disease, who were not treated by hormonal therapy or chemotherapy. Before therapy was started and at the end of therapy reactivity in the leukocyte migration inhibition test (LMI-Test) against autologous and homologous tumor tissue, serum levels of TNF alpha, IL-2 and IFN alpha, as well as the differentiation of different lymphocyte subsets in the peripheral blood, were determined. In patients undergoing adjuvant therapy with tamoxifen an increase of reactivity in the LMI test against tumor tissue (14.6% before and 22.9% after tamoxifen therapy) and increase of the percentage of NK cells (13.6% before and 19.8% after therapy) could be observed, whereas with TNF alpha, IL-2 and IFN alpha serum levels, as well as the differentiation of other lymphocyte subsets, no differences were found. In breast cancer patients with disseminated disease treated with high-dose MPA no changes of LMI reactivity and cytokine serum levels could be observed. We only found a decrease of T-helper cells from 38.4% before to 22.7% (p less than 0.05) at the end of therapy. These results indicate that tamoxifen has no severe suppressive side effects on different parameters of cell-mediated immunity and possibly leads to an increase in the number of NK cells. Contrary to this, high-dose MPA must be considered as a depletor of T-helper cells.

Aged↗