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The structure and absolute configuration of pseurotin (1), a new metabolite, isolated from culture filtrates of Pseudeurotium ovalis STOLK (Ascomycetes), has been shown to be 2‐[1′(S), 2′ (S)‐dihydroxhex‐3′‐ene‐yl]‐3‐methyl‐8(S)‐methoxy‐8‐benzoyl‐9(R)‐hydroxy‐(5S)‐1‐oxa‐7‐aza‐spiro[4.4]non‐2‐ene‐4, 6‐dione (1), by spectral data and chemical transformations, and by X‐ray analysis of its dibromo derivative 2 [1].

Cyclosporin A (CsA, Sandimmune) is known to reverse P-glycoprotein (P-gp170)-mediated multidrug resistance as efficiently as other prototype compounds of resistance modifiers. The immunosuppressive activity and nephrotoxicity of CsA, however, may limit its clinical use. PSC-833, a new cyclosporine, exerts a similar resistance-modifying activity but lacks toxicity or immunosuppressive activity. We have tested its potency in vitro and in vivo on the L1210 leukemia cell line transfected with a full-length cDNA copy of the human mdr I gene, which showed a stable 30-fold resistance towards adriamycin as compared to the parental cell line. In vitro growth of the transfected cell was unchanged. In vivo growth was less aggressive; the survival time of inoculated mice was prolonged. In vitro, PSC-833 was at least as potent as CsA or verapamil in reversing multidrug resistance. In vivo, the drug-resistant L1210 leukemia was completely unresponsive to i.v. monotherapy with adriamycin at its maximum tolerated dose (MTD). PSC-833 enhanced the activity and toxicity of adriamycin. The MTD of adriamycin was about 3 times lower than when given alone. On this basis, the MTD of i.v. adriamycin in combination with oral PSC-833 successfully overcame refractoriness to treatment. Survival times of the mice were considerably prolonged and even some cures of leukemic mice occurred.

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