Effect of medroxyprogesterone acetate on DMBA-induced rat mammary carcinoma and on immunological reactivity

The antineoplastic activity of medroxyprogesterone acetate (MPA) was investigated in rats bearing DMBA-induced mammary carcinomas, a classical model of hormone-dependent tumor. Using a repeated injection schedule of relatively short duration, MPA was markedly effective (80% CR + PR) not only on relatively small (1–1.5 cm) tumors but also on advanced (4.5–5.5 cm) neoplasms. MPA effectiveness was comparable to that of a frankly toxic adriamycin regimen. In antitumorally effective schedules MPA was incapable of significantly affecting in either direction cellular and humoral immunological reactivities in rodents.     

Experiences with doxo/epirubicin and medroxyprogesterone acetate (MPA) in prostatic cancer

Maximal androgen blockade (MAB) has been reported to prolong the time to progression and the duration of survival in metastatic prostatic cancer. The addition of epirubicin to MAB in such patients seems to improve the therapeutic results further. The beneficial effect of combining castration with epirubicin in metastatic cases appears questionable. In comparing the time to progession in patients treated with MAB±epirubicin versus castration ±epirubicin or estramustine, many studies reveal similar figures. Whether the results after treatment are actually improved remains controversial. In hormone-refractory cases, medroxyprogesterone acetate (MPA) alone seems superior to estramustine or prednisolone treatment. Combining MPA and epirubicin improves the results, but even if the improvement is of clinical value, it is nonetheless of limited magnitude.Paper presented at the 5th International Conference on Treatment of Urinary Tract Tumors with Adriamycin/Farmorubicin, 24–25 September 1993, Hakone, Japan     

Combined and sequential treatment using FCE 21336, a new prolactin-lowering drug,and medroxyprogesterone acetate (MPA) in DMBA-induced tumors in rats

The effect of the new, prolactin-lowering ergoline derivative FCE 21336 and medroxyprogesterone acetate (MPA) given alone and in combination was tested on DMBA-induced mammary tumors in rats. FCE 21336 (0.05 and 0.4 mg/kg p.o.) and MPA (25 and 50 mg/kg s.c.), administered 5 days/week for 4 weeks, inhibited the growth of established tumors and reduced serum prolactin levels. Combined treatment inhibited tumor growth more than single treatment. These results were confirmed in a second experiment: the antitumor effect of the combination of FCE 21336 (0.1 mg/kg p.o.) and MPA (50 mg/kg s.c.) was greater than that of the single treatment and was similar to the effect of ovariectomy. In this experiment rats with tumors that did not respond to 4 weeks' treatment with FCE 21336 (0.1 mg/kg p.o.) were treated during the next 4 weeks with MPA (50 mg/kg s.c.). MPA was effective on FCE 21336-unresponsive tumors. These data indicate that combined FCE 21336 and MPA treatment is more effective than single treatment and that MPA is effective on tumors not sensitive to the prolactin-lowering drug.     

A randomized comparison of megestrol acetate (MA) and medroxyprogesterone acetate (MPA) in patients with advanced breast cancer

The efficacy and side-effects of megestrol acetate and medroxyprogesterone acetate in postmenopausal patients with advanced breast cancer were compared in a prospectively randomized study. The dosage of MA was 2 × 80 mg p.o. or MPA 2 × 500 mg p.o. daily, given as a secondary hormonal treatment, mostly after previous treatment with tamoxifen.Ninety-eight patients entered the study and 92 were evaluable for effect, 48 patients on MA and 44 on MPA. Age, main tumor site and prior treatment were not different, but there was a preponderance of ER-negative tumors in the MA group. Responses appeared to be more frequent in the MPA-treated group (25% vs. 43%), predominantly in bone lesions, 12% for MA and 45% for MPA. Median progression-free survival was comparable, 15 vs. 10 months, and overall survival was not different (20 vs. 16 months).Toxicity was frequent, occurring in 83% vs. 74% of patients: increased appetite, nausea and dizziness in more than 20%, and a preponderance of pyrosis and breathlessness on MA and hot flashes, sweating and tremors on MPA. Cushingoid symptoms were present in about a quarter of the patients treated for more than 3 months. The occurrence of thrombo-embolic episodes and cardiovascular events was evenly distributed. Patients on MPA had more often increase in body weight, systolic blood pressure and serum creatinine than those treated with MA.It is concluded that MPA may be more effective for treatment of bone metastases, at the expense of more progestational side-effects. The occurrence of Cushingoid effects is frequent but similar in both arms, while the incidence of cardiovascular or thrombo-embolic events cannot be related to the use of either compound.     

High-dose medroxyprogesterone acetate (MPA) treatment in advanced breast cancer. A review.

Medroxyprogesterone acetate (MPA) when employed at high doses (greater than or equal to 500 greater than or equal to 1000 mg/day i.m.) can produce objective remission with improved survival in about 30% of postmenopausal women with advanced breast cancer resistant to cytotoxic drugs and endocrine therapies. When administered to women not previously treated with chemotherapy, the objective remission response rate reached 40%. From available evidence, high dose MPA can be considered a useful agent in the treatment of advanced breast cancer in postmenopausal women with soft tissue, pulmonary, pleural or osseous involvement even when patients have become refractory to prior hormone and cytotoxic therapies. Early results suggest that the response rate can be increased in patients with estrogen and/or progesterone-positive receptors. It is note worthy that in a study conducted on postmenopausal women resistant to cytotoxic and/or hormonal drugs, the median duration of survival was 13.5 months, while CRs plus PRs did not reach the median at 24 months after starting MPA treatment. High dose MPA is essentially devoid of major side effects. Relief of pain, increase in appetite and body weight, and sense of well being are characteristic features of the improved quality of life under MPA treatment. However, a gluteal abscess (from 2% to 20% dose related) is the most frequent side effect. A promising area for future studies is combined therapy using hormonal and cytotoxic agents or alternating sequential combinations. Well-designed studies are needed to develop means for increasing the complete response rate and therefore survival. Recent studies of combined chemo- and hormonal (MPA) therapy have yielded objective tumor regressions of 53 to 80% with an increased rate of complete remissions and duration of response.     

Benefits of medroxyprogesterone acetate (MPA) in advanced or recurrent breast cancer with higher serum concentration

The efficacy of medroxyprogesterone acetate (MPA) therapy in controlling progressive measurable metastatic breast cancer was assessed in 61 patients. In addition serum MPA concentrations were measured by high performance liquid chromatography (HPLC) and subjective effects of treatment were monitored. Overall 24 patients (39.3%) achieved an objective response(2 complete responses [ CR ] and 22 partial responses [ PR ]). There was no significant relationships between response to therapy and menopausal status, metastatic sites, previous therapy, histological type, or disease-free interval. Patients with estrogen (ER) and progesterone (PgR) receptor-positive tumors responded more frequently. Significant differences in serum MPA concentrations were seen between responders and non-responders, objective tumor shrinkage being seen in patients with serum levels in excess of 55 ng/ml. There were few cases responding to the therapy with serum MPA concentrations lower than 25 ng/ml. The serum MPA levels significantly correlated with an improvement in the performance status and survival. Patients with serum MPA concentrations lower than 25 ng/ml had significantly poorer survival. There was a significant relationship between MPA level and dose per area of boby surface (mg/ m(2)) in cases with CR or PR or no change (NC). However, the serum levels of patients with progressive disease despite therapy were lower than the expected levels based on the body surface area. This study demonstrated that serum MPA concentration is a determining factor for therapeutic benefit in advanced or recurrent breast cancer.     

Oral high-dose medroxyprogesterone acetate (MPA) treatment: cortisol/MPA serum profiles in relation to breast cancer regression

Medroxyprogesterone acetate (MPA), a potent synthetic progestin, has been widely used in the hormonal treatment of advanced breast cancer, but presently with varying dose schedules. The availability of a sensitive RIA-method for determination of serum MPA has stimulated the research on MPA serum levels in patients after repeated MPA administration. The aim of this study was to assay blood level profiles of MPA as well as of cortisol during repeated high-dose orally administered MPA. 34 patients with metastatic breast cancer were enrolled in this study. 12 patients died already within the first 4 weeks of MPA treatment due to multiple metastases. The dosage regimen based on the daily oral administration of 1,000 mg MPA suspension. During MPA treatment, a decrease of cortisol serum levels was observed in nearly all patients. Within the observation time of 8 months out of 22 evaluable cases 18.2% responded to the therapy (complete and partial response). No change was observed in 36.4% and progression in 45.5% of the patients. Within the remission (complete and partial) group, a good correlation between constant MPA serum levels above 150 ng/ml and remission was observed. But in the groups with no change and progression no such correlation could be observed.     

Controlled release low dose medroxyprogesterone acetate (MPA) inhibits the development of mammary tumors induced by dimethyl-benz(a) anthracene in the rat

Summary Medroxyprogesterone acetate (MPA) is well recognized to have beneficial effects for the treatment of advanced breast cancer which are comparable to those achieved with other forms of endocrine therapy. Using mammary tumors induced in the rat by dimethylbenz(a)anthracene (DMBA) as a model, we have studied the possibility that low dose MPA could prevent the development of these tumors. Single subcutaneous injection of Depo-Provera (crystalline suspension of MPA) or MPA encapsulated in biodegradable microspheres of 50 : 50 poly[DL-lactide-co-glycolide] was given 7 days before oral DMBA. While 63% of intact animals developed palpable mammary tumors within 85 days after DMBA administration, tumor incidence decreased to 28% and 23% in animals who had received 30 mg and 100 mg of Depo-Provera, respectively. The same amounts of MPA delivered in microspheres caused a further decrease in tumor incidence to respective values of 7% and 6%. Average tumor area, on the other hand, decreased from 4.89 cm² in intact rats to about 0.75 (0.57–0.88) cm² and approximately 0.20 (0.14–0.22) cm² in the Depo-Provera and microsphere-treated groups, respectively. Using the 50 : 50 formulation of poly[DL-lactide-co-glycolide] designed to release MPA at a constant rate for a 4-month period, the serum MPA concentration at 3 months was measured at 4.99 ± 0.43 ng/ml. Such data suggest that administration of a low dose controlled-release formulation of MPA in 50 : 50 poly[DL-lactide-co-glycolide] microspheres could well be an efficient and well tolerated approach for the prevention of breast cancer in women.     

A double blind placebo controlled trial of medroxyprogesterone acetate (MPA) in cancer cachexia.

Patients with breast cancer treated with MPA often report an improvement in appetite. Similar appetite stimulation is seen in patients treated with some corticosteroids, but MPA has a potential advantage over these drugs in that it does not exert a catabolic effect. MPA (100 mg tds orally) has therefore been compared with placebo in 60 patients with advanced malignant disease. Twenty-one patients in the MPA group and 20 in the placebo group were receiving chemotherapy. Patients were treated for 6 weeks and were assessed at weeks 0, 3 and 6 for appetite, energy, mood and pain using visual analogue scales. Nutritional status was assessed by the measurement of serum proteins and anthropometrics. Karnofsky score was recorded as a measure of performance status. There was a significant improvement in appetite in the MPA group between weeks 0 (pre-study) and 3 (P = 0.0002) and 0 and 6 (P = 0.015). There was no significant improvement in appetite in the placebo group. Supporting this finding was the significant increase in serum thyroid binding pre-albumin and retinol binding protein in the MPA group between weeks 0 and 3 and 0 and 6 (P = 0.023 and P = 0.039 respectively). These two parameters showed no significant change in the placebo group. There was no change in anthropometric measurements, weight, performance status, energy, mood or pain in either group. These data indicate that there was a significant increase in appetite in anorexic patients with advanced cancer treated with MPA which was reflected in increases in rapid turnover proteins reported to reflect nutritional status. However, this apparent increase in appetite did not result in improved weight, performance status, energy levels, mood or relief of pain. Further studies to investigate the effect of higher doses of MPA are indicated.     

The pharmacokinetics of high-dose medroxyprogesterone acetate (MPA) in the therapy of advanced breast cancer

Summary Oral MPA 1.5 g/day leads to plasma concentrations between 1 and 12 g/ml, with a broad intra-and interindividual variance. The plateau state is reached in between 4 and 16 days. Plasma concentrations in the plateau state are very sensitive to dose modifications. After cessation of administration, the decline in plasma levels seems to proceed in two phases, with half-times of about 20 h and 4 days. Extraction procedures reveal no benefit in discriminating between MPA and its metabolites.     

Promoter effect of medroxyprogesterone acetate (MPA) in N-methyl-N- nitrosourea (MNU) induced mammary tumors in BALB/c mice

The promoter effect of medroxyprogesterone acetate (MPA) on mammary carcinogenesis in female BALB/c mice was investigated using methylnitrosourea (MNU) as initiator. Nine out of 43 animals developed mammary carcinomas in the group treated with MNU (50 mg/kg) and MPA (administration of 40 mg every 3 months) starting 1 week after MNU administration. No tumors appeared in controls receiving only MNU or MPA during the time course of the experiment (9 months). The tumors were lobular adenocarcinomas showing different degrees of squamous differentiation with low or undetectable estrogen and progesterone receptors, and expressing epidermal growth factor receptors. These results support the hypothesis that MPA promotes the growth of MNU induced lesions.      

Pharmacokinetic study of low- versus high-dose medroxyprogesterone acetate (MPA) in women

The present study was conducted to compare the pharmacokinetics (PK) of low-dose versus high-dose medroxyprogesterone (MPA) as a once-daily oral administration. Of 32 patients, all women, enrolled in this PK study, 18 received 600 mg MPA daily and 14 received 1200 mg daily. Detailed PK data were obtained on day 1 and after more than 4 weeks of MPA treatment. In addition, multiple data for the minimum steady-state concentration (Css min) were analyzed. The MPA serum concentrations were measured by high-performance liquid chromatography. Wide interpatient variability was found in the PK parameters obtained both on day 1 and after more than 4 weeks. There were no clear relationships between the oral dose and the MPA peak concentration (Cmax), area under the time versus concentration curve (AUC), or mean Css min. Weight gains of 10% or more were demonstrated more frequently in the high-dose group (P<0.01). Liver dysfunction (n=5) did not influence the PK of MPA. Five patients demonstrated extremely low AUC and Cmax (<10 ng/ml) values on day 1. Phenobarbital, dexamethasone and betamethasone were being taken concomitantly with the MPA each by one patient. The serum MPA concentrations were markedly increased after the discontinuation of phenobarbital in that patient, suggesting a drug interaction. At present we cannot recommend the high dose of MPA, except in clinical studies, from a PK or a pharmacodynamic points of view. Received: 2 May 1997 / Accepted: 13 October 1997     

A case of inflammatory breast cancer treated with medroxyprogesterone acetate (MPA) in combination with intra-arterial infusion chemotherapy]

A 55-year-old female with severe inflammatory breast cancer was treated with the combined use of MPA and the intraarterial infusion chemotherapy. One cycle consisted of 4'-epi-adriamycin; 210 mg (day 1, 4 and 8) and daily administration of MPA; 1,200 mg. A marked shrinkage of the tumor was obtained with this treatment. The regressive change was noted not only in the primary lesion but in lymph nodes of the axillary region. Therefore, the combined use of MPA with intra-arterial infusion chemotherapy may well contribute to the treatment of inflammatory breast cancer.     

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.     

Effect of medroxyprogesterone acetate (MPA) and serum factors on cell proliferation in primary cultures of an MPA-induced mammary adenocarcinoma

Summary The effect of progesterone (Pg), medroxyprogesterone acetate (MPA), estradiol (E₂), dihydrotestosterone (DHT) and dexamethasone (DEXA) was studied on thein vitro growth rate of a progestin-dependent (PD), estrogen-sensitive mammary tumor line originated in an MPA-treated BALB/c mouse (C4-HD), and on its estrogen-resistant variant (C4-HDR). The specificity of hormone action was further investigated using the anti-hormones RU-486 and hydroxyflutamide (FLU). Cell growth was evaluated in epithelial and fibroblastenriched cultures using³H-thymidine and/or autoradiography and immunocytochemistry. The results indicate that cell growth is directly stimulated by MPA and Pg at concentrations ranging from 10^–11 to 10^–7 M. RU486 prevented MPA-induced stimulation in concentrations 10 to 100 fold lower than those of MPA. When used alone, it inhibited cell proliferation only in concentrations higher than 10^–11 M. At nM concentrations, neither DEXA nor DHT stimulated³H-thyrnidine uptake except DEXA at 100 nM. MPA-induced stimulation was not reverted by micromolar concentrations of FLU. As for E₂ (10^–7–10^–9 M) it prevented MPA stimulation only in cultures of estrogen-sensitive tumors. Progesterone receptors (PR) (475 ± 115 fmoles/10⁵ cells, n = 5) and estrogen receptors (ER) (ND-115 fmoles/10⁵ cells, n = 5) were detected only in epithelial-enriched cultures. Serum from 7 day-MPA-treated mice induced a significant increase of³H-thymidine uptake; an increase was also obtained with serum from untreated ovariectomized animals to which 1 nM-100 nM concentrations of MPA had been added. The stimulatory effect of the exogenous MPA was much lower than that of the serum obtained from MPA-treated animals.It is concluded that MPA stimulates cell growth of primary cultures of MPA-induced PD tumors via PR. The results provide support for a direct effect of MPA which may be mediated or potentiated by serum factors.     

The clinical effect of medroxyprogesterone (MPA) in elderly patients with lung cancer

Eighty-nine patients over 70 years old with untreated lung cancer, of various cell type and in various stages, were randomly assigned to chemotherapy (CT) alone or CT combined with medroxyprogesterone acetate (MPA). CT consisted of cisplatin, 60 mg/m2 i.v., along with etoposide (VP-16), 150 mg/m2 i.v., on day 1. The VP-16 was increased to 200 mg/m2, orally, on day 3. The entire regimen was given every 4 weeks for a maximum of six cycles. MPA was administered in daily 500-mg doses, i.m., 5 days a week for 1 month, followed by 1000 mg i.m., once a week, for 5 months. Changes in body weight and appetite were documented. After two cycles of CT, 64 patients were found to be evaluable for response. Forty-five had non-small-cell lung cancer (NSCLC) and 19 had small-cell lung cancer (SCLC). Thirty-seven patients had received CT alone and 27 CT plus MPA. In NSCLC, the objective response to CT alone was 36% versus 37% with CT plus MPA. In SCLC, the corresponding figures were 63% and 22%. The overall objective response rate was 60% in NSCLC and 48% in SCLC. Median survival using CT alone was 10 months for NSCLC patients and 11 months for SCLC patients. Using CT plus MPA, it was 10 months for NSCLC patients and 7 months for SCLC patients. In the control arm, 1-year survival was 42% for NSCLC patients and 48% for SCLC patients; in those who were given MPA, it was 48% for NSCLC patients and 9% for SCLC patients. Improved appetite and weight gain were reported more frequently by MPA patients, and they did not complain of CT's usual side effects. The fact that MPA had no significant effect on CT response or survival in patients also treated with a combination of cisplatin and VP-16, along with the small survival advantage for the control group in SCLC patients, suggests that combining MPA and CT may result in improved quality of life.     

A phase III trial of oral high-dose medroxyprogesterone acetate (MPA) versus mepitiostane in advanced postmenopausal breast cancer

A randomized controlled trial was performed to compare the therapeutic results of oral high-dose medroxyprogesterone acetate (HD-MPA) versus mepitiostane (MS) in the treatment of postmenopausal breast cancer. MPA was given at three doses of 400 mg orally daily to 47 patients and produced objective responses in 19 cases (40.4%). An objective response was seen in 14 of the 40 control patients given MS at two doses of 10 mg orally daily (35.0%). Among patients with bone metastases, 6 of 19 (31.6%) for HD-MPA and 2 of 13 (15.4%) for MS showed objective responses. The other merits of HD-MPA suggested in the study were improvement in performance status, increase in appetite, and myeloprotective effect.     

Mammary carcinogenesis induced byN-methyl-N-nitrosourea (MNU) and medroxyprogesterone acetate (MPA) inBALB/c mice

Summary MPA induces mammary tumors in virgin BALB/c mice with an average latency of 52 weeks. In order to determine whether the simultaneous administration of a chemical carcinogen, N-methyl-N-nitrosourea (MNU), shortened the latency of MPA-induced tumors, a total of 60 virgin female BALB/c mice were treated with either MNU+MPA or MNU or MPA. The experiment lasted 7 months. The incidence and latency of mammary tumors were significantly different between the 3 groups: 15/19 (79%) in MNU+MPA-treated mice with a latency of 154±19 days; 3/20 (15%) in MNU-treated mice with a latency of 179±7 days; 0/20 (tumors only start appearing after 10 months) in MPA-treated mice. Histologically, MNU+MPA-induced tumors were similar to the few tumors observed in MNU-treated mice: most of them were type B adenocarcinomas with a high degree of necrosis and calcification. Only one of the MNU+MPA-induced tumors expressed high levels of ER and PR and proved to be MPA-responsive in further passages. All the other tumors showed low or non-detectable levels of ER and PR together with an independent pattern of tumor growth. In MNU-treated mice the only tumor that was transplanted proved to be hormone independent and had low levels of PR and ER. In both MNU and MNU+MPA treated mice lung adenocarcinomas were detected. Cystic uterine glandular hyperplasias were observed in all animals. It can be concluded that MPA and MNU potentiate their carcinogenic effect in mammary gland.Abbreviations MPA Medroxyprogesterone Acetate - MNU N-methyl-N-nitrosourea - ER Estrogen Receptors - PR Progesterone Receptors     

A case of marked effectiveness using medroxyprogesterone acetate (MPA) in lung metastases of cancer of the uterine body

This case is a 71-year-old female. As hormonotherapy, 400 mg/day of MPA alone was orally administered in a lung metastatic case of cancer of the uterine body in the IV stage. Although progressing for 2 years and 1 month after the initial administration, lung metastatic foci disappeared, and recurrence was not noted, and serious side effect by using MPA was also not noted. Progesterone therapy such this case is considered as one of therapeutic methods which can be expected remarkably effective rate in the lu metastatic foci of cancer of the uterine body.