Introduction: In addition to being commonly used as antibiotics, tetracyclines have also been demonstrated to be potent inhibitors of tumor angiogenesis. In 1995, Weingart reported that minocycline, a semisynthetic tetracycline, is synergistic with the alkylating agent carmustine in prolonging survival of rats implanted with 9L intracranial gliosarcoma. In this study, we evaluate the effectiveness of minocycline as adjuvant therapy to two common methods of treating glioblastoma: oral temozolomide and radiotherapy.
Previously, antiangiogensis agents delivered systemically have not been shown in vivo to be synergistic with radiation when treating intracranial tumors either in animals or people. We hypothesize the blood-brain barrier inhibited their action. In contrast to these studies, we deliver minocycline intracranially using drug-impregnated wafers and then irradiate the rats.
Methods: We assessed the effects of minocycline-impregnated wafers combined with either alkylating agents or radiation on glioma in rats. Forty-eight rats were divided into 5 groups: no treatment, minocycline, temozolomide, minocycline+temozolomide, radiation, and minocycline+radiation. All rats were implanted with intracranial 9L gliosarcoma on day 0. On day 5, animals received a controlled-release polymer containing minocycline and/or radiotherapy (20Gy). Temozolomide (100-mg/rat) was administered orally on days 5-9. Survival was the primary endpoint.
Results: Control animals had median survival of 15 days, while oral temozolomide and intracranial minocycline had median survivals of 19 (p=0.002) and 20 (p=0.003) days, respectively. The combination of the two agents increased survival by 127% with a median survival of 32 days (p<0.001). Radiation alone increased median survival to 35 (p<0.001) days, while the combination of radiation and intracranial minocycline increased survival to 68 (p<0.001) days.
Conclusions: Our results show that minocycline delivered intracranially is statistically synergistic with oral temozolomide. Furthermore, the results suggest that antiangiogenic agents delivered intracranially may be an effective way to improve radiation treatment for brain cancers.
Patient Care: This is preclinical data that demonstrates increased efficacy when minocycline is added to the clinically utilized treatments of temozolomide and radiation therapy.
Learning Objectives: The reader will learn that the tetracycline, minocycline, when delivered intracranially may have beneficial effects on efficacy in a rodent gliosarcoma model.