Inhibition of Ras and related guanosine triphosphate-dependent proteins asa therapeutic strategy for blocking malignant glioma growth: II - Preclinical studies in a nude mouse model

OBJECTIVE: Preliminary studies have demonstrated that the Ras family and re lated guanosine triphosphate-dependent proteins are overactivated in malign ant gliomas and that inhibition of the activation of such proteins, by bloc kade of their post-translational processing, reduces tumor cell growth in v itro. The current study evaluates the utility of this therapeutic strategy in vivo, using preclinical glioma model systems. METHODS: We examined the efficacy against U-87 human malignant glioma cells , in both subcutaneous and intracranial nude mouse models, of selective pep tidomimetic inhibitors of farnesyltransferase (FTI-276) and geranylgeranylt ransferase (GGTI-297), which are involved in critical steps in the post-tra nslational processing of Ras and related guanosine triphosphate-dependent p roteins. For the subcutaneous model, 2 x 10(5) U-87 cells were implanted; a fter measurable tumors were detected on Day 7, animals were treated with ei ther FTI-276, GGTI-297, or vehicle, administered by continuous infusion for 7 days. Differences in tumor volumes among the treatment groups were exami ned for significance using a Student's t test. For the intracranial model, 2 x 10(5) U-87 cells were implanted in the right frontal lobe and treatment was initiated on Day 7. In initial studies, animals received a 7-day cours e of either FTI-276, GGTI-297, or vehicle, In subsequent studies, a 28-day treatment period was used. Comparisons of survival times among treatment gr oups were performed using a rank-sum test. RESULTS: Although the two agents exhibited comparable antiproliferative act ivities in previous in vitro studies, an obvious difference in efficacy was apparent in this study. Whereas the geranylgeranyltransferase inhibitor fa iled to improve survival rates, compared with those observed for control an imals, in either the subcutaneous or intracranial model, the farnesyltransf erase inhibitor produced objective regression of tumor growth in the subcut aneous model and significant prolongation of survival times in the intracra nial model, without apparent toxicity. In the subcutaneous model, tumor vol umes for the control, GGTI-297-treated, and FTI-276-treated animals on Day 28 after implantation were 621 +/- 420, 107 +/- 104, and 18.5 +/- 12.7 mm(3 ), respectively (P < 0.05). In the 7-day-treated intracranial model, surviv al times for the control, GGTI-297-treated, and FTI-276-treated groups were 27.7 +/- 2.9, 29.8 +/- 2.1, and 43.6 +/- 2.7 days, respectively (P < 0.001 ). In the 28-day-treated intracranial model, survival times for the control , GGTI-297-treated, and FTI-276-treated groups were 29.2 +/- 3.7, 28.3 +/- 3.9, and 58.7 +/- 6.2 days, respectively, with five of six animals in the l atter group surviving more than 55 days after tumor implantation (P < 0.001 ). CONCLUSION: These studies demonstrate that farnesyltransferase inhibition i s effective in diminishing the growth of human glioma cells in vivo. Evalua tion of this treatment approach in clinical trials is warranted.