Activity of cyclosporins as resistance modifiers in primary cultures of human haematological and solid tumours.
The semiautomated fluorimetric microculture cytotoxicity assay (FMCA) was used for evaluation of the ability of cyclosporin A (CsA) and its novel non-immunosuppressive derivative SDZ PSC 833 (PSC) to modify the response to doxorubicin or vincristine in vitro in different haematological and solid human tumour types. Primary cultures of 322 tumour samples were analysed. Both cyclosporins showed resistance-modifying activity in all haematological tumours tested, and in solid tumours activity was observed in ovarian carcinoma and childhood tumours. Little or no effect was found in the remaining tumour types, including breast, renal and adrenal cortical carcinomas and adult sarcomas. In most of the responsive cases the interaction between the modifier and the cytotoxic drug was synergistic. There was a tendency to higher activity in samples from previously treated patients, and an inverse relationship between degree of cytotoxic drug resistance and resistance-modifying activity was noted. No difference in potency between CsA and PSC could be discerned. The results indicate differential in vitro resistance-modifying activity of the cyclosporins depending on tumour type. The results also suggest that treatment with resistance modifiers should be considered also for primary therapy of drug-sensitive tumours. Drug resistance assays such as the FMCA may become useful in preclinical evaluation of resistance modifiers.
Division of Clinical Pharmacology, University Hospital, Uppsala University, Sweden.
H
H
Fridborg
B
B
Jonsson
P
P
Nygren
K
K
Csoka
K
K
Nilsson
G
G
Oberg
J
J
Kristensen
J
J
Bergh
B
B
Tholander
L
L
Olsen
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002648:Child; D016572:Cyclosporine / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D004357:Drug Synergism; D005260:Female; D005470:Fluorometry / Q000379:methods; D006801:Humans; D007945:Leukemia, Lymphoid / Q000188:drug therapy; D007951:Leukemia, Myeloid / Q000188:drug therapy; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D003524:Cyclosporins; D014750:Vincristine; D004317:Doxorubicin; D016572:Cyclosporine; C070272:valspodar