SDZ PSC-833--a novel potent in vitro chemosensitizer in multiple myeloma.
Multiple myeloma cell lines and patient tumor samples with and without the expression of the classical multidrug resistance (MDR) phenotype were investigated in vitro for drug induced cytotoxicity and modulation of drug resistance. Overall there was a good correlation in the cell lines between MDR expression, as measured by immunocytochemistry with monoclonal antibodies against P-glycoprotein 170 (Pgp), and in vitro resistance to doxorubicin (dox) and vincristin (vcr). Drug resistance in the cell line RPMI 8226 dox 40, expressing a high level of Pgp, was almost completely reversed by the novel non-immunosuppressive cyclosporin A (CsA) analog SDZ PSC-833 (PSC), while the chemosensitizers verapamil, CsA and quinine, in clinically achievable concentrations, were much less effective. In cell lines with low Pgp expression, PSC and the other chemosensitizers seem equally effective. The patient tumor samples were selected to represent different combinations of Pgp expression, drug resistance and effects of chemosensitizers. PSC and CsA appeared equally potent and resistance modulation was detected not only in Pgp positive, but also in Pgp negative tumor samples. Furthermore, in one case of a Pgp expression myeloma, chemosensitizers were without effect. These findings indicate the need to incorporate in vitro chemosensitivity assays with Pgp determination when the effects of MDR modulating chemosensitizers are to be studied in the clinic.
Division of Clinical Pharmacology, University Hospital, Uppsala University, Sweden.
B
B
Jonsson
K
K
Nilsson
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P
Nygren
R
R
Larsson
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001853:Bone Marrow / Q000473:pathology; D016572:Cyclosporine / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D004357:Drug Synergism; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology; D009101:Multiple Myeloma / Q000188:drug therapy*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D003524:Cyclosporins; D008562:Membrane Glycoproteins; D014750:Vincristine; D004317:Doxorubicin; D016572:Cyclosporine; C070272:valspodar