Antitumor effect of avermectins.

The effect of a mixture of naturally occurring aversectin C and avermectin B(1) on the growth of ascites and solid experimental tumors of mice was studied. It was shown for the first time that avermectins possess a pronounced antitumor action. When added at nontoxic doses, they significantly suppressed the growth of ascites Ehrlich carcinoma and P388 lympholeukemia and solid Ehrlich and 755 carcinomata.

Avermectins inhibit multidrug resistance of tumor cells.

The modification of the sensitivity of Hep-2 and P388 tumor cells to taxol and vincristine, substrates of multidrug resistance proteins, by naturally occurring avermectins and the effect of avermectins on the accumulation of calcein in cells and the efflux of rhodamine 123 were studied. While avermectins did not affect the sensitivity of tumor cells to hydrogen peroxide and cisplatin, they significantly enhanced the sensitivity of cells of both wild-type and resistant strains to taxol and vincristine. The coefficients of modification for resistant strains were substantially higher.

Effect of avermectins on Ca2+-dependent Cl- currents in plasmalemma of Chara corallina cells.

A natural complex of avermectins, aversectin C, and a component of this complex, avermectin A1, were shown to change the conductivity of Ca2+-dependent Cl- channels of plasmalemma of Chara corallina cells by acting from the outer side of the cellular membrane. Low concentrations of aversectin C and avermectin A1 increased the Cl- current: K1/2 = 35 ng/ml for the whole complex and K1/2 = 21 pg/ml for A1. Relatively high concentrations of the compounds suppressed the Cl- current: K1/2 = 2.

Selective cytostatic and neurotoxic effects of avermectins and activation of the GABAalpha receptors.

A natural avermectin complex, aversectin C, was shown to be capable of exerting selective cytostatic and neurotoxic effects on mammalian cells. Specifically, it killed proliferating neuroblastoma B103 cells but was non-toxic for differentiated cells of this culture. The antiproliferation action of aversectin C was not inhibited by bicuculline or picrotoxin, antagonists of the GABAalpha receptors, and was partly due to the action of avermectin A1, a component of aversectin C.