An Orthotopic Model of Glioblastoma Is Resistant to Radiodynamic Therapy with 5-AminoLevulinic Acid.

Abstract

Simple SummaryRadiosensitization of glioblastoma is a major ambition to increase the survival of this incurable cancer. Before surgery, oral administration of 5-aminolevulinic acid leads to the accumulation of fluorescent protoporphyrin IX, preferentially in the cancer cells rather than in the normal brain. This property is used to optimize the resection of the tumor under fluorescent light. Protoporphyrin IX may also carry radiosensitization activity. To test this hypothesis, we designed a robust murine preclinical model of glioblastoma with tumors implanted into the brain of mice treated by fractionated radiotherapy, as for humans. Despite the specific accumulation of porphyrins in glioblastoma, there was no radiosensitization. We confirmed these results in in vitro 3D patient-derived spheroids. Radiosensitization by molecules such as porphyrins needs more exploration for application in glioblastoma treatment.Radiosensitization of glioblastoma is a major ambition to increase the survival of this incurable cancer. The 5-aminolevulinic acid (5-ALA) is metabolized by the heme biosynthesis pathway. 5-ALA overload leads to the accumulation of the intermediate fluorescent metabolite protoporphyrin IX (PpIX) with a radiosensitization potential, never tested in a relevant model of glioblastoma. We used a patient-derived tumor cell line grafted orthotopically to create a brain tumor model. We evaluated tumor growth and tumor burden after different regimens of encephalic multifractionated radiation therapy with or without 5-ALA. A fractionation scheme of 5 × 2 Gy three times a week resulted in intermediate survival [48–62 days] compared to 0 Gy (15–24 days), 3 × 2 Gy (41–47 days) and, 5 × 3 Gy (73–83 days). Survival was correlated to tumor growth. Tumor growth and survival were similar after 5 × 2 Gy irradiations, regardless of 5-ALA treatment (RT group (53–67 days), RT+5-ALA group (40–74 days), HR = 1.57, p = 0.24). Spheroid growth and survival were diminished by radiotherapy in vitro, unchanged by 5-ALA pre-treatment, confirming the in vivo results. The analysis of two additional stem-like patient-derived cell lines confirmed the absence of radiosensitization by 5-ALA. Our study shows for the first time that in a preclinical tumor model relevant to human glioblastoma, treated as in clinical routine, 5-ALA administration, although leading to important accumulation of PpIX, does not potentiate radiotherapy.