Effect of hyperthermia on the action of cis-diamminedichloroplatinum(II), rhodamine 123(2) [tetrachloroplatinum(II)], rhodamine 123, and potassium tetrachloroplatinate in vitro and in vivo.
Platinum rhodamine 123 [Pt(Rh-123)2] was synthesized in an effort to produce a new drug which would have the selective uptake into carcinoma cells of Rh-123 and the alkylating and radiosensitizing properties of the chloroplatinum moiety. Because both Rh-123 and cis-diamminedichloroplatinum(II) (CDDP) have been shown to become more cytotoxic at elevated temperatures, we tested the interactions between Pt(Rh-123)2 and hyperthermia both in EMT6 cells in vitro and in the Lewis lung carcinoma in vivo. In the EMT6 cells, CDDP was far more cytotoxic than Pt(Rh-123)2 at 37 degrees C, but its cytotoxicity was less enhanced by exposure of cells to the drug at 42 degrees C than was true for Pt(Rh-123)2 [about 2 logs of increased killing at 42 degrees C after exposure to 10 microM CDDP versus over 3 logs of increased killing at 42 degrees C after exposure to 500 microM Pt(Rh-123)2]. Both Rh-123 and K2PtCl4 also are more cytotoxic to EMT6 cells at 42 degrees C than at 37 degrees C, but the hyperthermic enhancement was far less striking. In the Lewis lung carcinoma, the growth delay produced by CDDP (8 mg/kg) increased by a factor of approximately 2.5 when the drug was given i.p. just prior to local heating of the s.c. thigh tumor to 43 degrees C for 30 min, but the growth delay produced by Pt(Rh-123)2 (100 mg/kg) given i.p. 1 h before local hyperthermia increased by a factor of 5. In contrast, K2PtCl4 and Rh-123 given i.p. produced very short growth delays at normal temperatures and these growth delays were not enhanced by hyperthermia. The effect of these drugs at 37 degrees C and 42 degrees C on the conformation of superhelical pBR322 DNA was also examined. Exposure to CDDP caused progressive alteration from the supercoiled to the linear form of the DNA over time. In contrast, Pt(Rh-123)2 apparently produced progressive degradation of the DNA. Hyperthermia did not alter the qualitative damage produced by the drugs but increased the rate at which the changes occurred. These results suggest both that Pt(Rh-123)2 probably has a different mechanism of action at the DNA than does CDDP and that Pt(Rh-123)2 may be a good drug to use with local hyperthermia and radiation.
Herman
T S
TS
Joint Center for Radiation Therapy, Harvard Medical School, Boston, Massachusetts 02115.
Teicher
B A
BA
Chan
V
V
Collins
L S
LS
Kaufmann
M E
ME
Loh
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002712:Chlorides / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D006358:Hot Temperature; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000628:therapy; D009690:Nucleic Acid Conformation; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D010984:Platinum / Q000494:pharmacology*; D017671:Platinum Compounds; D020112:Rhodamine 123; D012235:Rhodamines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014966:Xanthenes / Q000494:pharmacology*
D000970:Antineoplastic Agents; D002712:Chlorides; D009944:Organoplatinum Compounds; D017671:Platinum Compounds; D012235:Rhodamines; D014966:Xanthenes; C050316:tetrachloroplatinate dianion-rhodamine-123 complex; C036919:tetrachloroplatinate; D020112:Rhodamine 123; D010984:Platinum; D002945:Cisplatin