Reversal of the human and murine multidrug-resistance phenotype with megestrol acetate

Abstract

MA is an orally active PG derivative with an excellent safety profile that is used primarily for the treatment of carcinomas of the breast and endometrium. We investigated the potential application of MA as an MDR-reversal agent using cell culture and human tumor xenograft models. The reversing activity of MA in vitro was compared with that of PG and VER in two human MDR cell lines, the colon carcinoma HCT-116/VM46 and the breast carcinoma MCF-7/ADR, and in a murine cell line, J774.2. At concentrations as low as 3 microM, MA was capable of partially restoring sensitivity to Act D in the HCT-116/VM46 cells and sensitivity to DOX in the MCF-7/ADR cells. Although less effective than VER, MA was about 2.5 times more potent than PG in reversing MDR at equimolar concentrations. Increased accumulation of DOX in drug-resistant cells that were treated simultaneously with MA was observed by flow cytometry. In vivo, using established human colon and breast carcinoma xenografts implanted s.c. in athymic mice, the combined therapy with MA and DOX resulted in enhanced antitumor activity relative to that of DOX alone in the MDR sublines. These results suggest that MA may be a promising clinical MDR-reversing agent.

Results of a phase III, double-blind, placebo-controlled trial of megestrol acetate modulation of P-glycoprotein-mediated drug resistance in the first-line management of small-cell lung carcinoma

“…P-gp expression is associated with resistance to a number of natural and semisynthetic cytotoxic drugs in vitro including the anthracyclines, mitomycin C, vinca alkaloids, epipodophyllotoxins and actinomycin D (Chin et al, 1993). P-gp-mediated drug resistance can be modulated by a number of chemically dissimilar drugs, including verapamil, quinine, quinidine, cyclosporin A and hydrophobic steroids, such as progesterone or megestrol acetate (MA) (Wang et al, 1991;Fleming et al, 1992;Bellamy and Dalton, 1994), thereby decreasing drug resistance. Clinically, there are practical difficulties in the routine clinical use of the majority of these drugs because of significant toxicities.…”

Reversal effects of nomegestrol acetate on multidrug resistance in adriamycin-resistant MCF7 breast cancer cell line

“…MG is a strong reversal agent: its capacity to increase intracellular accumulation of vincristine is 2-3-fold that of progesterone [6]. Previous results have shown that a daily dose of 800 mg MG resulted in a plasma concentration of 2 μM [21]; however, to reverse MDR, 5 μM is necessary in theory. Because high doses of MG induce vomiting, oedema, dizziness and androgen-like side-effects, the ideal effective concentration is difficult to obtain in vivo .…”

“…The reversal mechanism consists of, for example, binding directly to P-gp, inhibiting the transport function of drug efflux, increasing the intracellular accumulation of the drug and changing lipid mobility in the plasma membrane [4, 10, 11, 12]. However, different compounds have different mechanisms.…”

In VivoModel Systems in P-Glycoprotein-Mediated Multidrug Resistance

“…94,98,[121][122][123][124][125][126][127][128][129][130] Paired human cell lines used as xenografts are described in the Tables 7 and 8. [131][132][133][134][135][136][137][138][139][140][141][142][143][144] In the ideal situation, modulators of MDR do not enhance cytotoxicity in parental tumors, while enhanced antitumor effects can be observed in MDR tumors. It should be noted that even in the most often used tumor model, the P388 leukemia, this is not the case, because the parental P388 cell line expresses low levels of P-glycoprotein and is sensitive to reversal activity.…”