title: Multifactorial molecular mechanisms are involved in resistance of preirradiated human cervix carcinoma cells to cis-dichlorodiammineplatinum (II) and vincristine.
abstract: We previously found that human cervix carcinoma HeLa cells irradiated with multiple fractions of gamma rays (0.5 Gy daily, five times per week over 6 weeks) become resistant to cis-dichlorodiammineplatinum(II) (cis-DDP), methotrexate (MTX) and vincristine (VCR), but retain the same sensitivity to gamma rays or UV light. In the present report attempts were made to elucidate the mechanisms by which these cells have acquired resistance to cis-DDP and VCR. The sensitivity to different drugs was measured by modified MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method. Neither buthionine sulfoximine (BSO) nor ethacrinic acid were able to reverse the resistance of preirradiated cells to cis-DDP. Therefore, neither the increased levels of glutathione nor glutathione transferase seem to be involved in resistance to cis-DDP. Preirradiated cells did show resistance to cadmium, indicating the increased levels of metallothioneins in these cells. Resistance of preirradiated cells to vincristine was abolished by the addition of verapamil, indicating that resistance to this drug may depend on the increased expression of plasma membrane P-glycoprotein. It was concluded that mechanisms of resistance of preirradiated cells to cytostatics are multifactorial and involve at least the increased levels of metallothioneins and changes in the plasma membrane. Acquired resistance to cytotoxic drugs induced by preirradiation may be the reason for the reduced response to these drugs after radiation treatment of certain tumors.
authors.affiliation: Department of Experimental Biology and Medicine, Ruder Boskovic' Zagreb, Croatia.
authors.forename: M
authors.initials: M
authors.lastname: Osmak
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D019328:Buthionine Sulfoximine; D002104:Cadmium / Q000494:pharmacology; D019256:Cadmium Chloride; D002352:Carrier Proteins / Q000502:physiology; D002712:Chlorides / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000502:physiology / Q000528:radiation effects; D004976:Ethacrynic Acid / Q000494:pharmacology; D005260:Female; D005720:Gamma Rays; D005978:Glutathione / Q000502:physiology; D005982:Glutathione Transferase / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000502:physiology; D008668:Metallothionein / Q000502:physiology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D014466:Ultraviolet Rays; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic; D002352:Carrier Proteins; D002712:Chlorides; D008562:Membrane Glycoproteins; D002104:Cadmium; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D014750:Vincristine; D008668:Metallothionein; D014700:Verapamil; D005982:Glutathione Transferase; D005978:Glutathione; D019256:Cadmium Chloride; D004976:Ethacrynic Acid; D002945:Cisplatin