Sulfoquinovosyl acylpropanediol (SQAP): Inhibition of poly(ADP-ribose) metabolism and enhanced cytotoxicity in homologous recombination repair-deficient Chinese hamster-derived cells.

Sulfoquinovosyl acylpropanediol (SQAP; a synthetic derivative of the sulfoglycolipid natural product sulfoquinovosyl acylglycerol, SQAG), has anti-tumor and radiosensitizing activities in tumor xenograft mouse models. Here, we have studied the PARP inhibitory activity of SQAP and synthetic lethality in BRCA2-deficient cells. In initial screening studies with DNA repair-deficient Chinese hamster ovary cells, homologous recombination repair-deficient cell lines showed increased sensitivity to SQAP, compared to wild-type cells or other DNA repair-deficient mutants. Chinese hamster lung V79 cells and the derivative cell lines V-C8 (BRCA2-deficient) and V-C8 + BRCA2 gene corrections were used to test the role of BRCA2 in SQAP cytotoxicity. The findings were confirmed in studies of the human colon cancer cell lines DLD-1 and its BRCA2-knockout derivative. SQAP inhibited the enzymes poly(ADP-ribose) polymerase (PARP) and poly(ADP-ribose) glycohydrolase (PARG). SQAP pretreatment decreased H2O2induced poly(ADP-ribose) formation in V79 cells. SQAP caused DNA double-strand breaks and chromosome aberrations in V79 BRCA2-mutated cells but did not affect cells in the G2 phase. We have demonstrated that SQAP induces synthetic lethality in BRCA2-deficient Chinese hamster-derived cells via its effects on poly(ADP-ribose) metabolism, motivating further examination of its therapeutic potential, especially against tumors that are deficient in homologous recombination repair due to mutations in BRCA2 or other genes.

Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis.

OBJECTIVE: To evaluate the efficacy and safety of perampanel in patients with sporadic amyotrophic lateral sclerosis (SALS). METHODS: This randomized, double-blind, placebo-controlled, multicenter, phase 2 clinical study was conducted at 12 sites. Patients with probable or definite ALS as defined by revised El Escorial criteria were enrolled. Sixty-six patients were randomly assigned (1:1:1) to receive placebo, 4 mg perampanel, or 8 mg perampanel daily for 48 weeks. Adverse events (AEs) were recorded throughout the trial period. The primary efficacy outcome was the change in Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R) score after 48 weeks of treatment. RESULTS: One patient withdrew before starting the treatment. Of 65 patients included, 18 of 22 patients randomized to placebo (82%), 14 of 22 patients randomized to 4 mg perampanel (64%), and 7 of 21 patients randomized to 8 mg perampanel (33%) completed the trial. There was a significant difference in the change of ALSFRS-R scores [- 8.4 (95% CI - 13.9 to - 2.9); p = 0.015] between the placebo and the perampanel 8 mg group, primarily due to worsening of the bulbar subscore in the perampanel 8 mg group. Serious AEs were more frequent in the perampanel 8 mg group than in the placebo group (p = 0.0483). CONCLUSIONS: Perampanel was associated with a significant decline in ALSFRS-R score and was linked to worsening of the bulbar subscore in the 8 mg group.