Telomerase activity correlates with growth of transplantable osteosarcomasin rats treated with cis-diammine dichloroplatinum or the angiogenesis inhibitor AGM-1470

To determine the role of telomerase activity in the growth of tumors in rat s undergoing chemotherapy a comparison of the volumes of telomerase-positiv e transplantable osteosarcomas was made in rats treated with the antineopla stic agent cis-diammine dichloroplatinum (CDDP) or the angiogenesis inhibit or O-(chloroacetylcarbamoyl)fumagillol (AGM-1470). Male F344 rats, 8 weeks old, received transplants of macroscopic lung metastatic nodules into the s ubcutaneous hack space and treatment was started on day 14 thereafter CDDP was injected i.v. at doses of 0, 0.625, 1.25 and 2.5 mg/kg body weight (b.w .) and AGM-1470 was administered at total doses of 0, 2.5, 5 and 10 mg/kg b .w. over 2 weeks by osmotic pumps, also implanted into the subcutaneous bac k space, but remote from the transplanted tumors. On day 28, ail animals we re killed for measurement of transplanted tumor size and determination of t elomerase activities by telomeric repeat amplification protocol (TRAP) assa y. The results showed telomerase activity to be highly correlated with the treated/non-treated (T/C) tumor size ratio (r = 0.96, P<0.0001). In a secon d experiment, CDDP at 2.5 mg/kg b.w and AGM-1470 at 10 mg/kg b.w., these be ing the most effective doses, were given as in the first experiment, and an imals were serially killed on days 14, 21, 28, 35 and 42. Tumors in rats tr eated with CDDP and AGM-1470 showed 18.2% and 20.5% of the control telomera se activity on days 35 and 21, respectively, when tumor growth was inhibite d. However, on day 42, the activities increased to 46.5% and 92.5%, this co rrelating with re-growth (r = 0.73, P<0.0001). These results suggest that d ecline of telomerase activity may be involved in tumor growth retardation i nduced by chemotherapeutic agents. This possibility clearly warrants furthe r mechanistic studies.