Collateral sensitivity to thaliblastine and/or hyperthermia exhibited by a rat ovarian tumor cell line selected for resistance to cisplatin.
Drug resistance severely limits the effectiveness of clinical cancer chemotherapy. Employment of drugs other than the selected compounds with different mechanisms of action may provide a potential way to improve the therapeutic effects. Thaliblastine (TBL), a natural compound, showed a 2-fold higher cytotoxicity in a cisplatin (DDP) resistant rat ovarian tumor cell line (0-342/DDP) than in its parental sensitive line (0-342), as determined by an antiproliferation assay with 24 h continuous exposure. This phenomenon was also observed following 2 h pulse exposure if combined with heat treatment (40 degrees C). Further escalation of the temperature to 43 degrees C alone brought about 74.7 +/- 17.0% growth inhibition in the sensitive and 97.2 +/- 1.8% in the resistant line. Under this condition, the ID50 of TBL was again only half as much in 0-342/DDP cells as in the parental cells (12 vs 24 micrograms/ml) when compared to the hyperthermic treatment alone. In a colony formation assay with 2 h pulse exposure, the hypersensitivity of the resistant cells to DDP and/or heat was further confirmed. Alkaline elution showed that 24 h continuous treatment with TBL induced DNA single-strand breaks (SSB) in a dose-dependent manner in 0-342/DDP cells, whereas there was almost no DNA-SSB production by TBL in the sensitive line, possibly in part accounting for the hypersensitivity of the DDP resistant cells to TBL. The heat treatment (40 degrees C for 2 h) induced SSB in both lines, which was further enhanced by combination with TBL. This damage was repaired in part in 0-342 but almost completely in 0-342/DDP line after cells grew in drug-free medium for 48 h following the exposure, indicating that resistant cells can more efficiently repair DNA damage by either TBL or hyperthermia. Altogether, these results suggest that TBL may have potential to be used clinically as an alternative in the treatment of cisplatin-resistant malignancies with hyperthermia.
Chen
G
G
Institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg.
Zeller
W J
WJ
Todorov
D K
DK
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001060:Aporphines / Q000494:pharmacology*; D044182:Benzylisoquinolines; D002945:Cisplatin / Q000494:pharmacology; D003131:Combined Modality Therapy; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005038:Ethylnitrosourea; D005260:Female; D006979:Hyperthermia, Induced; D007546:Isoquinolines / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000628:therapy*; D051381:Rats; D013696:Temperature; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000972:Antineoplastic Agents, Phytogenic; D001060:Aporphines; D044182:Benzylisoquinolines; D004273:DNA, Neoplasm; D007546:Isoquinolines; C073328:thalicarpine; D005038:Ethylnitrosourea; D002945:Cisplatin