DNA-damaging activity of the cyproterone acetate analogues chlormadinone acetate and megestrol acetate in rat liver

The synthetic progestin cyproterone acetate (CPA) has been recentlyshown to elicit DNA repair synthesis in cultured rat hepatocytesand to form adducts with rat hepatocyte DNA in vitro and invivo. In the present study we have examined the genotoxic potentialof the structural analogues of CPA, chlormadinone acetate (CMA)and megestrol acetate (MGA) in rat liver cells. CPA stronglyinduced DNA repair synthesis in hepatocyte cultures from femalesbut not from males. In contrast, CMA and MGA (2–50 µM)did not detectably increase repair synthesis in cultured hepatocytesfrom either gender. CMA and MGA, however, caused the formationof DNA adducts detectable by the ³²P-postIabeIling technique.At a concentration of 30 µM, between 30 and 50 adducts/10⁹nucleotides were found with MGA and CMA in cultured hepatocytesof female rats, and between 5 and 20 adducts/10⁹ nucleotideswere found in hepatocytes of males. By comparison, 30 µMCPA had been found to produce 1670 adducts/10⁹ nucleotides inhepatocytes from female rats. CMA and MGA also induced low levelsof DNA adducts in vivo. When female rats were treated with 100mg/kg of CMA or MGA per os, the adduct levels were 2 and 19adducts/10⁹ nucleotides respectively. The results indicate thatboth CMA and MGA show some genotoxicity in rat liver cells,which is, however, much lower than that for CPA. Our findingsfurther suggest that the high genotoxicity of CPA is associatedwith the presence of the l, 2     

Treatment of stage D prostatic carcinoma with megestrol acetate

Nine previously untreated patients with stage D prostatic carcinoma received megestrol acetate 40 mg orally three times daily. Responses included five partial regressions, two stabilizations, and two progressions. Duration of response ranged from 3 + to 33 + months, with a mean of 11.7 months and a median of 12 months. Three of five patients who had failed prior hormonal therapy remained objectively stable while receiving megestrol acetate. No gastrointestinal toxicity, gynecomastia, fluid retention, or thromboembolic complications were observed during treatment. Weight gain of 5 to 51 pounds occurred in seven of 14 patients.     

Augmentation of vincristine cytotoxicity by megestrol acetate

 Purpose: To determine the effect of a semisynthetic progesterone, megestrol acetate (MA), on the cytotoxicity of various chemotherapeutic agents including vincristine, doxorubicin, actinomycin-D, taxol, vinblastine and colchicine in cell lines with or without P-gp expression. Methods: Three cell lines with high P-gp expression (two colon cancer and one leukemia), and a control cell line with no P-gp expression were exposed to chemotherapeutic agents in the presence or absence of MA and drug sensitivity was determined using the MTT colorimetric assay. P-gp-170 expression was detected by flow cytometry using JSB-1 monoclonal antibody and the functionality of MDR expression was tested by rhodamine-123 uptake studies. In vitro drug accumulation studies were performed using [³H]-vincristine. The results were subjected to paired t-test analysis and 95% confidence intervals were determined in cytotoxicity tests. Results: MA augmented the cytotoxicity of vincristine, but not doxorubicin, actinomycin-D, taxol, vinblastine or colchicine in the three P-gp-expressing cell lines, whereas verapamil augmented the cytotoxicity of doxorubicin and vincristine. MA did not augment the cytotoxicity of vincristine in the P-gp-negative HUT-102 cell line. Conclusion: MA augmented vincristine cytotoxicity in P-gp-expressing cell lines. However, this phenomenon did not occur with the other classic MDR drugs. Therefore, the augmentation of vincristine cytotoxicity by MA can be explained either by involvement of a different mechanism that coexists with the mdr-1 phenotype or by the presence of a different affinity or binding site on the P-gp molecule for MA compared to that for the other classic MDR drugs and verapamil. Received: 8 September 1995 / Accepted: 3 June 1996     

Tamoxifen and megestrol acetate for postmenopausal breast cancer

AIM: To compare the effects of tamoxifen and megestrol acetate on liver proteins, androgens, and glucocorticoids during adjuvant treatment for postmenopausal breast cancer. METHODS: A subgroup of women within a large prospective multicenter trial were followed with blood sampling every 3 mo during 2 yr. Women were randomized to receive either continuous tamoxifen 40 mg/d or repeated sequential treatment with tamoxifen and megestrol acetate (MA) 160 mg/d. RESULTS: We found profound and distinct differences between the two regimens. Tamoxifen increased steroid-binding proteins (SHBG and CBG) and suppressed circulating androgens and IGF-I. In contrast, the metabolic effects of tamoxifen were clearly antagonized by MA. There was a rise in IGF-I and marked suppression of steroid-binding proteins. Levels of free testosterone were reduced by 70%. MA also caused apparent adrenal suppression. CONCLUSION: The different effects on anabolic/catabolic balance and adrenal function may relate to certain clinical effects during treatment.     

Comparative study of DNA repair induced by cyproterone acetate, chlormadinone acetate and megestrol acetate in primary cultures of human and rat hepatocytes

Cyproterone acetate (CPA), a synthetic progestin recently foundto induce genotoxic effects in hepatocytes from female ratsand from humans of both genders, and two structural analogues,chlormadinone acetate (CMA) and megestrol acetate (MGA), havebeen compared for their capacity to induce DNA repair synthesisas measured by quantitative autoradiography. Exposure of primaryhuman hepatocytes for 20 h to concentrations of CPA, CMA andMGA ranging from 2 to 50 uM induced positive responses in culturesfrom donors of both genders and the amounts of DNA repair elicitedby the three progestins were similar. Under the same experimentalconditions substantial differences were observed in the amountsof DNA repair elicited by the three progestins in primary hepatocytesfrom female rats, their potency decreasing in the followingorder CP>> CM>> MGA, and the three compounds failedto induce DNA repair in hepatocytes from male rats. These results,which agree with previous findings, suggest that for these sexsteroids extrapolation to humans of results obtained in ratsmight be questionable.     

Mammary nodules in dogs during four years' treatment with megestrol acetate or chlormadinone acetate

A 7 year study of megestrol and chlormadinone in female dogs is in progress. This report characterized histopathologically 60 mammary nodules during the first 4 years of the study. 100 purebred female beagles, 6-12 months of age, were randomly assigned to 5 equal groups. One group was used as a control. Oral doses were .01, .10, and .25 mg/kg/day of megestrol acetate in coconut oil in capsules and of chlormadinone acetate .25 mg/kg/day in lactose tablets. These doses were 1, 10, and 25 times the projected dose of megestrol for humans and about 25 times the human dose of chlormadinone. After 2 years 4 dogs from each group were necropsied. One high-dose megestrol-treated and 1 chlormadinone-treated dog had benign mixed mammary tumors. Palpable nodules were first observed at 16 months in the chlormadinone-treated dogs, at 18 months in dogs given the high dose megestrol and at 27 months in the dogs treated with middle-dose megestrol. Transitory nodules were found in 4 control dogs after 21 months and in low dose megestrol-treated dogs at 26 months. Of 38 grossly detected nodules evaluated microscopically from the megestrol-treated dogs 27 were nodular hyperplasia, 5 were benign mixed mammary tumors, 3 were ductal dialatations, 1 was a lymph node, 1 was fat necrosis and 1 was the umbilicus. Of 22 nodules from the chlormadinone-treated dogs 12 were nodular hyperplasia, 4 benign mixed mammary tumors, 1 chondromucoid degeneration and 1 adenocarcinoma with widespread metastases. 3 nodules were lymph nodes and 1 other had no mammary tissue. Involutions, regression and sclerosis of many areas of nodular hyperplasia were evident at 4 years. Thus of the 60 nodules evaluated during the first 4 years of the study 50 were non-neoplastic and 10 were neoplastic. It is considered that the 1 adenocarcinoma may have been spontaneous and not a treatment-related neoplasm. A precursor stage through nodular hyperplasia apparently did not occur.     

Randomized comparison of the effects of tamoxifen, megestrol acetate, or tamoxifen plus megestrol acetate on treatment response and survival in patients with metastatic breast cancer

BACKGROUND:: The antioestrogen tamoxifen and progestins act via differentreceptors and may therefore have complementary effects againsthuman breast cancer. This possibility was tested in a randomizedstudy which compared the effects of tamoxifen, standard-dosemegestrol acetate, and these two agents in combination, in patientswith metastatic breast cancer. PATIENTS AND METHODS:: 184 post-menopausal patients with metastatic breast cancer wererandomized to initial treatment with either tamoxifen (TAM)40 mg daily, megestrol acetate (MA) 160 mgm daily, or the combinationof the two administered simultaneously. Patients crossed overto the alternative single agent on relapse or disease progression.Patients were evaluated for response, time to initial and ultimatetreatment failure, and survival. RESULTS:: There were no significant differences between the three groupswith respect to response rates, nor the other parameters. Patientsurvival was significantly associated with age >60 years,ER positive status, and the absence of visceral metastases. CONCLUSIONS:: TAM and MA are both equally effective in response inductionas initial treatments and the combination has no advantage.Sequential treatment is still optimal, TAM being the preferredinitial agent in view of the reported side effects with MA. breast, cancer, megestrol acetate, randomized, trial, tamoxifen     

Treatment of advanced breast cancer with megestrol acetate after therapy with tamoxifen

The efficacy of megestrol acetate in the treatment of advanced (Stage IV) carcinoma of the breast was studied in 48 evaluable patients who had been initially treated with tamoxifen. Forty-five patients had previously responded to the tamoxifen therapy. Fifteen patients (31%) had partial remissions, sixteen patients (33%) had stable disease, and seventeen patients (36%) had progressively disease. The median response duration was seven months for responding patients and six months for disease-stable patients. These results suggest that megestrol acetate is an effective agent for the palliation of advanced breast cancer relapsing following response to tamoxifen therapy.     

Influence of aminoglutethimide on the metabolism of medroxyprogesterone acetate and megestrol acetate in postmenopausal patients with advanced breast cancer

Summary In this study the influence of aminoglutethimide (AG) on the disposition of medroxyprogesterone acetate (MPA) and megestrol acetate (MA) was studied. When 1,000 mg AG daily was supplementally given to six patients on chronic treatment with MPA (1,000 mg/day) or MA (160 mg/day), mean serum levels of progestin were reduced by 74% as compared with control levels (P<0.03). AG did not change the blood clearance rate of MPA when the latter was given i. v. This discrepancy between AG's influence on oral and parenteral progestin disposition could be explained by pharmacokinetic properties of the progestins, and our results suggest that AG stimulates the metabolism of progestins. The decrease in MPA and MA serum levels was accompanied by an increase in serum cortisol, sex hormone-binding globulin (SHBG) and testosterone levels. This suggests that AG reduces the biological activity of progestins.     

奥氮平联合醋酸甲地孕酮治疗晚期癌症性厌食症的疗效观察

目的:观察奥氮平联合醋酸甲地孕酮治疗晚期癌症性厌食症的疗效。方法:将85例癌性厌食患者随机分至治疗组（奥氮平联合醋酸甲地孕酮组+营养支持）和对照组（醋酸甲地孕酮组+营养支持）及单纯营养支持组,观察各组治疗前后食欲、体重、卡氏评分和免疫功能的变化并评价不良反应。结果:治疗结束后,治疗组食欲、卡氏评分改善率分别为82.8%、69.0%,对照组分别为65.5%、34.4%,空白组分别为40.7%、33.3%,治疗组改善率明显高于对照组和空白组（P＜0.05）;治疗组在体重、血清白蛋白、免疫功能改善程度方面均优于对照组和空白组（P＜0.05）。未见明显不良反应。结论:奥氮平联合醋酸甲地孕酮能有效改善晚期恶性肿瘤患者厌食症状,是治疗晚期恶性肿瘤患者有效辅助药物,药物不良反应小。     

Conservative therapy with metformin plus megestrol acetate for endometrial atypical hyperplasia

Objective

To compare the efficacy of metformin plus megestrol acetate (MA) with that of MA alone for treating endometrial atypical hyperplasia (EAH).

Methods

This pilot study included 16 EAH patients who met at least one metabolic syndrome (MS) criterion and received either adjunctive metformin plus MA (MET group) or MA monotherapy (MA group). Each patient in the MA group received 160 mg of MA daily, whereas patients in the MET group received the same dose of MA plus 0.5 g of metformin thrice daily. Treatment response was assessed by histological examination of dilation and curettage specimens obtained after 12 weeks of therapy.

Results

Each group had eight patients, and half of the patients in each group were diagnosed with MS. The complete response (CR) rate was 75% (6/8) in the MET group and 25% (2/8) in the MA group (p=0.105). Complications of MS did not affect the response rates in either group. In the MET group, 75% (3/4) of the patients had CR in the presence or absence of MS. In the MA group, 50% (2/4) of the patients with MS had CR, whereas no patient without MS had CR. No irreversible toxicities were observed.

Conclusion

Metformin plus MA may be a potential alternative therapy for treating EAH, and the MS status of patients may have no effect on the efficacy of metformin plus MA therapy.     

Induction of micronuclei and initiation of enzyme-altered foci in the liver of female rats treated with cyproterone acetate, chlormadinone acetate or megestrol acetate

The synthetic anti-androgen and progestin cyproterone acetate(CPA), recently found to be genotoxic for the liver, and twostructurally similar progestins, chlormadinone acetate (CMA)and megestrol acetate (MGA), have been compared for clastogenicand tumor-initiating activities in female rats. In the micronucleusassay, carried out in rats given a single p.o. dose of 100 mg/kg,CPA induced the maximum increase in the frequency of micronucleatedhepatocytes (6.6-fold as compared to controls) when treatmentwas performed 3 days before partial hepatectomy and cell sampling2 days later. Under the same experimental conditions the clastogenicpotencies of CMA and MGA were 69% and 36% of that of CPA respectively.In the liver foci assay, p.o. dosing with 100 mg/kg CPA oncea week for 6 successive weeks induced, as compared to controls,a significant increase in the number and area of     

Characterization of tropane alkaloid aromatic esters that reverse the multidrug-resistance phenotype

P-Glycoprotein (Pgp) associated multidrug-resistance (MDR) is a significant factor that can lead to the failure of cancer chemotherapy. Several new tropane alkaloid aromatic esters obtained from extracts of Erythroxylum pervillei Baillon (Erythroxylaceae) (1-8) and Erythroxylum rotundifolium Lunan (Erythroxylaceae) (9-12) by means of bioassay-directed fractionation were found to restore vinblastine sensitivity with cultured multidrug-resistant KB-VI cells. With this model, growth was not inhibited by addition of vinblastine (1 microg/ml) to the culture medium, but in combination with tropane alkaloids, inhibition was observed with IC50 values categorized as: low (ranging from 0.17-0.62 microM) for 1 [3alpha-phenylacetoxy-6beta-(3,4,5-trimethaxycinnamoyloxy)-tropane], 3 [3alpha-(3,4,5-trimethoxybenzoyloxy)-6beta-(3,4,5-trimethoxycinnamoyloxy)tropane], 4 [3alpha-(3,4,5-trimethoxybenzoyloxy)-6beta-(3,4,5-trimethoxycinnamoyloxy)-7beta-hydroxytropane], 5 [3alpha,6beta-di-(3,4,5-trimethoxycinnamoyloxy)tropane], 6 [3alpha,6beta-di-(3,4,5-trimethoxycinnamoyloxy)-7beta-hydroxytropane] and 9 [6beta-benzoyloxy-3alpha-(3,4,5-trimethoxycinnamoyloxy)tropane]; medium (2.0-3.7 microM) for 2 [3alpha-(3-hydroxyphenylacetoxy)-6beta-(3,4,5-trimethoxycinnamoyloxy)tropane] and 10 [7beta-acetoxy-6beta-benzoyloxy-3alpha-(3,4,5-trimethoxycinnamoyloxy)tropane]; or high (9.8 microM) for 11 [6beta-benzoyloxy-3alpha-(3,4,5-trimethoxycinnamoyloxy)tropane-7beta-ol]. Compounds 7 (tropane-3alpha,6beta,7beta-triol 3-phenylacetate), 8 (1alphaH, 5alphaH-tropan-3alpha-yl 3,4,5-trimethoxybenzoate) and 12 (6beta-(3,4,5-trimethoxybenzoyloxy)-3alpha-(3,4,5-trimethoxycinnamoyloxy)tropane-7beta-ol) were not active. Among the active compounds, 1 and 3-6 were further tested with drug-resistant CEM/VLB100 cells. In the presence of modulator, sensitivity to vinblastine increased by 50-5,000-fold. Treatment of KB-V1 cells with 1 or 3-6 enhanced the intracellular accumulation of fluorescence dye (rhodamine 123). Visualization by confocal microscopy confirmed the intracellular accumulation of rhodamine 123 in drug-resistant KB-V1 cells was significantly less than drug-sensitive KB-3 cells, while treatment of KB-V1 cells with 10 microM 4 significantly increased intracellular accumulation. The molecular characteristics of the isolates were then determined and compared with their potential to reverse drug resistance. ClogP and molar refractivity were weakly correlated with their potential to reverse MDR     

Phase I and pharmacokinetic study of vinblastine and high-dose megestrol acetate

PURPOSE: Preclinical data indicate that progestational agents (progesterone, medroxyprogesterone acetate and megestrol acetate) interact with p-glycoprotein (P-gp) and reverse P-gp-associated resistance to vinca alkaloids and other natural products. Based on these data, we performed a phase I study of high-dose oral megestrol acetate and vinblastine to evaluate the safety of this regimen. PATIENTS AND METHODS: Enrolled in the study were 61 patients with advanced solid tumors, refractory to standard therapy. Cohorts of patients received megestrol acetate according to the following escalation scheme (loading dose/maintenance dose, twice daily for 7 days): 750 mg/250 mg, 750 mg/375 mg, 1000 mg/500 mg, 1500 mg/1000 mg, 3000 mg/2000 mg, 4500 mg/3000 mg, 6000 mg/4000 mg, and 7500 mg/5000 mg. They also received 1.5 mg/m(2) per day of vinblastine by continuous infusion for 5 days (days 2 to 6). RESULTS: Of the 61 patients, 59 were evaluable for toxicity. A maximum tolerated dose (MTD) was not reached. The regimen was well tolerated. Of the 59 patients, 10 (17%) experienced grade 4 leukopenia. All of these cases were at dose levels 3 to 8. There was an increase in the steady-state concentration (Css) of megestrol acetate with increasing dose up to the sixth dose level. Further increases in the dose produced no change in the megestrol acetate Css. Only 2.4% of megestrol acetate was free in the plasma as compared to 65.6% in RPMI culture medium. Megestrol acetate administration was associated with profound suppression of ACTH and cortisol levels. CONCLUSIONS: The combination of vinblastine and megestrol acetate was well tolerated. An MTD for this combination was not achieved as a result of the saturable absorption of megestrol acetate. Although potentially therapeutic serum concentrations of megestrol acetate were achieved, it is unlikely that MDR was reversed given the high protein-binding of the drug. Profound suppression of the pituitary-adrenal axis was also observed during the administration of megestrol acetate.     

Effect of megestrol acetate or melengestrol acetate on preneoplastic and neoplastic mammary growth in mice

Pellets of megestrol acetate and melengestrol acetate were implanted subcutaneously every one and two months, respectively, into 3-5 month old SHN virgin mice. Spontaneous mammary tumourigenesis was significantly enhanced by both steroids. The formation of preneoplastic mammary hyperplastic alveolar nodules (HAN) was, in contrast, inhibited by both progestins. As these results closely resemble the effects of progesterone and of medroxyprogesterone acetate on the development of mammary tumours both in the SHN mouse and in the woman, it seems likely that this animal model may prove valuable for the study of human breast cancer that is no longer responsive to progestins.     

Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia

Preliminary information has suggested that megestrol acetate leads to appetite stimulation and nonfluid weight gain in patients with breast cancer, other cancers, and AIDS. Pursuant to this, we developed a randomized, double-blind, placebo-controlled trial of megestrol acetate in patients with cancer-associated anorexia and cachexia. We randomly assigned 133 eligible patients to receive 800 mg of megestrol acetate per day or a placebo. Patients assigned to megestrol acetate more frequently reported improved appetite (P = .003) and food intake (P = .009) when compared with patients receiving the placebo. A weight gain of 15 lb or more over baseline was seen in 11 of 67 (16%) patients receiving megestrol acetate compared with one of 66 (2%) given the placebo (P = .003). Patients receiving megestrol acetate reported significantly less nausea (13% vs. 38%; P = .001) and emesis (8% vs. 25%, P = .009). No clinically or statistically significant toxic reactions were ascribed to megestrol acetate, with the exception of mild edema. This study convincingly demonstrated that megestrol acetate can stimulate appetite and food intake in patients with anorexia and cachexia associated with cancer, leading to significant weight gain in a proportion of such patients.     

Complete remission of a brain metastasis to third-line hormonal treatment with megestrol acetate

The prognosis of patients with brain metastases from breast cancer is poor. Median survival after radiotherapy is 5-6 months. We report a patient in whom a complete response of a brain metastasis was induced by megestrol acetate at a daily dose of 160 mg orally.