Megestrol Acetate

Megestrol Acetate is a synthetic progesteronal and potent anti-estrogen agent with multiple drug actions [1].

Megestrol Acetate has been reported to cause minor reduction of tumor size and prolonged survival time in Hepatocellular carcinoma (HCC). In addition, Megestrol Acetate has shown the dose-dependent inhibition on growth of the human liver tumor cells in the HepG2 cell lines with the IC50 value of 260μM in vitro. Furthermore, Megestrol Acetate has also shown a significant suppression of tumor growth. The tumor volumes of the addition of Megestrol Acetate group regressed to 59% of controls at 6th week. Apart from these, Megestrol Acetate has been revealed to increase the cell numbers of sub-G1 and inhibit the cell cycle progression in both dose- and time–dependent fashion. Besides, Megestrol Acetate has been demonstrated to induce apoptosis of HepG2 cells [1].

References:
[1] Zhang K1, Chow PK. The effect of megestrol acetate on growth of HepG2 cells in vitro and in vivo. Clin Cancer Res. 2004 Aug 1; 10(15):5226-32.

Megestrol acetate improves cardiac function in a model of cancer cachexia-induced cardiomyopathy by autophagic modulation.[Pubmed:27239419]

J Cachexia Sarcopenia Muscle. 2016 Dec;7(5):555-566.

BACKGROUND: Cachexia is a complex metabolic syndrome associated with cancer. One of the features of cachexia is the loss of muscle mass, characterized by an imbalance between protein synthesis and protein degradation. Muscle atrophy is caused by the hyperactivation of some of the main cellular catabolic pathways, including autophagy. Cachexia also affects the cardiac muscle. As a consequence of the atrophy of the heart, cardiac function is impaired and mortality is increased. Anti-cachectic therapy in patients with cancer cachexia is so far limited to nutritional support and anabolic steroids. The use of the appetite stimulant Megestrol Acetate (MA) has been discussed as a treatment for cachexia. METHODS: In this study the effects of MA were tested in cachectic tumour-bearing rats (Yoshida AH-130 ascites hepatoma). Rats were treated daily with 100 mg/kg of MA or placebo starting one day after tumour inoculation, and for a period of 16 days. Body weight and body composition were assessed at baseline and at the end of the study. Cardiac function was analysed by echocardiography at baseline and at day 11. Locomotor activity and food intake were assessed before tumour inoculation and at day 11. Autophagic markers were assessed in gastrocnemius muscle and heart by western blot analysis. RESULTS: Treatment with 100 mg/kg/day MA significantly attenuated the loss of body weight (-9 +/- 12%, P < 0.05) and the wasting of lean and fat mass (-7.0 +/- 6% and -22.4 +/- 3 %, P < 0.001 and P < 0.05, respectively). Administration of 100 mg/kg/day MA significantly protected the heart from general atrophy (633.8 +/- 30 mg vs. placebo 474 +/- 13 mg, P < 0.001). Tumour-bearing rats displayed cardiac dysfunction, as indicated by the significant impairment of the left ventricular ejection fraction, the left ventricular fractional shortening, the stroke volume, the end dyastolic volume, and the end systolic volume. In contrast, MA significantly improved left ventricular ejection fraction, left ventricular fractional shortening, and left ventricular end systolic volume. Western blotting analysis showed an upregulation of the autophagic pathway in the gastrocnemius and hearts of the placebo-treated tumour-bearing rats. Treatment with MA, however, was able to modulate the autophagic markers (e.g. Beclin-1, p62, TRAF6, and LC3) in the gastrocnemius and in the hearts of tumour-bearing rats. Most importantly, 100 mg/kg/day MA reduced mortality [hazard ratio (HR): 0.44; 95%CI: 0.20-1.00; P = 0.0486]. CONCLUSIONS: Megestrol Acetate improved survival and reduced wasting through a marked downregulation of autophagy, occurring in both skeletal and heart muscle, the latter effect leading to a significant improvement of cardiac function. Our data suggest that MA might represent a valuable strategy to counteract the development of cancer cachexia-induced cardiomyopathy.

A Phase 2, Randomized, Open-Label Study of Irosustat Versus Megestrol Acetate in Advanced Endometrial Cancer.[Pubmed:27870712]

Int J Gynecol Cancer. 2017 Feb;27(2):258-266.

OBJECTIVE: Advanced/metastatic or recurrent endometrial cancer has a poor prognosis. Malignant endometrial tissue has high steroid sulphatase (STS) activity. The aim of this study was to evaluate STS as a therapeutic target in patients with endometrial cancer. METHODS: This was a phase 2, multicenter, international, open-label, randomized (1:1), 2-arm study of the STS inhibitor oral irosustat 40 mg/d versus oral Megestrol Acetate 160 mg/d in women with advanced/metastatic or recurrent estrogen receptor-positive endometrial cancer. The primary end point was the proportion of patients without progression or death 6 months after start of treatment. Secondary end points included progression-free survival, time to progression, overall survival, and safety. RESULTS: Seventy-one patients were treated (36 with irosustat, 35 with Megestrol Acetate). The study was prematurely stopped after futility analysis. Overall, 36.1% and 54.1% of patients receiving irosustat or Megestrol Acetate had not progressed or died at 6 months, respectively. There were no statistically significant differences between irosustat and Megestrol Acetate in response and overall survival rates. Irosustat patients had a median progression-free survival of 16 weeks (90% confidence interval, 9.0-31.4) versus 40 weeks (90% confidence interval, 16.3-64.0) in Megestrol Acetate patients. Treatment-related adverse events occurred in 20 (55.6%) and 13 (37.1%) patients receiving irosustat or megestrol, respectively. Most adverse events in both groups were grade 1 or 2. CONCLUSIONS: Although irosustat monotherapy did not attain a level of activity sufficient for further development in patients with advanced/recurrent endometrial cancer, this study confirms the activity of hormonal treatment (Megestrol Acetate) for this indication.

Quantitative Assessment of Food Effect on the Pharmacokinetics of Nano-Crystallized Megestrol Acetate.[Pubmed:27639080]

Basic Clin Pharmacol Toxicol. 2017 Mar;120(3):270-277.

Megestrol Acetate, an appetite stimulant with low bioavailability, shows increased bioavailability when taken together with food. However, the pharmacokinetic characteristics of Megestrol Acetate and its relation with food are not well understood. This study aimed to investigate the food effect on the pharmacokinetics (PK) of the recently developed nano-crystallized Megestrol Acetate (NCMA), using a model-based approach. Data were obtained from an NCMA PK study consisting of a single dose in fasting (39 individuals) and fed conditions (40 individuals). Plasma concentrations were measured up to 120 hr after dosing. With the incorporation of body-weight via allometry, NONMEM 7.3 was used to develop a PK model, which was then used to simulate an optimal fasting dose yielding an area under concentration (AUC) and maximum concentration (Cmax ) of NCMA close to those obtained with the fed dose. NCMA concentrations were best characterized by a two-compartment model with first-order absorption linked to a recycling compartment to account for the multiple concentration peaks observed. Food increased bioavailability 2.2 times and decreased the absorption rate constant 0.58 times. Recycling event times were estimated to be 3.56, 7.99 and 24.0 hr. The optimal fast dose was 2.0 times higher than the fed dose, and the resulting difference in drug exposure between the fasting and fed dose was 7.5%. This work suggests that the PK model developed can be applied to an optimal dosage regimen design for NCMA treatment.

Comparing the Administration of Letrozole and Megestrol Acetate in the Treatment of Women with Simple Endometrial Hyperplasia without Atypia: A Randomized Clinical Trial.[Pubmed:28353144]

Adv Ther. 2017 May;34(5):1211-1220.

INTRODUCTION: The present study was conducted as a pilot to compare the therapeutic effects and the potential side effects of oral Megestrol Acetate and Letrozole in the treatment of simple hyperplasia in perimenopausal women. METHODS: The participants of this randomized clinical trial consisted of two groups of 25 women aged 44-50 presenting with abnormal uterine bleeding diagnosed with simple endometrial hyperplasia without cytologic atypia confirmed by transvaginal ultrasonography and biopsy. The first group received 40-mg doses of Megestrol Acetate for 2 weeks per month for a total period of 2 months. The second group received 2.5-mg daily doses of Letrozole for a total period of 2 months. The differences in terms of quantitative measurements were analyzed using the independent two-sample t test and the paired t test. To compare the two groups in terms of the distribution of the categorical variables, Pearson's Chi square and Fisher's Exact tests were used at the significance level of 0.05 by Stata-9.2. RESULTS: Although the intervention led to significant improvements in both groups (P < .001), there was no difference between the groups in terms of accomplishing resolution (P = .74) [seven (28%) patients in the Letrozole group and five (20%) in the Megestrol group], while two patients in the Letrozole group and nine in the Megestrol group suffered from side effects, suggesting significantly lower side effects in the Letrozole group (P = .02). CONCLUSION: Letrozole and Megestrol Acetate seem to have similar effects on the treatment of simple endometrial hyperplasia, the only difference being that Letrozole presents fewer side effects than Megestrol Acetate in patients with this condition. FUNDING: Abnormal Uterine Bleeding Research Center of Semnan University of Medical Sciences, Semnan, Iran. TRIAL REGISTRATION: IRCT2015031011504N5.