Efficacy of Pt(Rh-123)2 as a radiosensitizer with fractionated X rays.
The complex of tetrachloroplatinate and rhodamine-123, Pt(Rh-123)2 has demonstrated cytotoxic and antitumor effects and radiosensitizing potential in vitro and in vivo. Using the FSaIIC in vivo-in vitro tumor system, tumor cell survival indicated a dose modifying factor (DMF) of 1.51 due to the addition of Pt(Rh-123)2. Pt(Rh-123)2 was added to two fractionated radiation protocols. The drug was administered by i.p. injection on three different multiple injection schedules, each reaching a cumulative dose of 75 mg/kg in those groups receiving the maximum treatment. Radiation was delivered in 3 Gy fractions in the morning and afternoon or daily for five days. Pt(Rh-123)2 was administered daily at 25 or 15 mg/kg or on alternate days at 25 mg/kg. The DMFs obtained ranged from 1.8 +/- 0.2 to 1.25 +/- 0.1. The pharmacokinetics of [195mPt]-Pt(Rh-123)2 after i.p. injection of 100 mg/kg of the drug were characterized in mice bearing the Lewis lung carcinoma using a two compartment model. The total exposure of the lung carcinoma to the drug as reflected by the area under the concentration vs. time curve was 1.5 times greater than that of the normal lung tissue. The formation of DNA cross-links and single strand breaks in SCC-25 cells exposed to Pt(Rh-123)2 (100 microM) and 6 Gy under normally oxygenated and hypoxic conditions immediately following treatment or 6 hours later were measured by DNA alkaline elution. Over the time course, the level of DNA cross-linking increased in the normally oxygenated cells by 1.5-fold and the hypoxic cells by 4-fold. The overall effects of Pt(Rh-123)2 in the presence of radiation results from both DNA cross-linking and single strand breaks.
D000818:Animals; D003131:Combined Modality Therapy; D007700:Kinetics; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy*; D009944:Organoplatinum Compounds / Q000378:metabolism / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000378:metabolism / Q000627:therapeutic use*; D011879:Radiotherapy Dosage; D012235:Rhodamines / Q000378:metabolism / Q000627:therapeutic use; D014018:Tissue Distribution
D009944:Organoplatinum Compounds; D011838:Radiation-Sensitizing Agents; D012235:Rhodamines; C050316:tetrachloroplatinate dianion-rhodamine-123 complex