Abstract 3730: Cisplatin treatment enhancement with acetaminophen in a model of human medulloblastoma in nude rats

Abstract

Abstract Purpose: To determine the efficacy of cisplatin treatment when enhanced by high dose acetaminophen (APAP) and followed by N-acetylcysteine (NAC) rescue in a nude rat model of medulloblastoma. Methods: Human medulloblastoma (DAOY) cells were inoculated into the cerebellum of female athymic nude rats (rnu/rnu). On day 10, rats were randomized to treatment groups (n = 6 per group): (1) saline controls; (2) IP cisplatin 2 mg/kg; (3) PO APAP 600 mg/kg + IP cisplatin; and (4) APAP + cisplatin + NAC 1 g/kg. All treatments were given twice a week for two weeks. Cisplatin treatment was given one hour after APAP, and NAC was given 4 hours following cisplatin. T2 and contrast-enhanced T1 magnetic resonance (MR) imaging sequences were performed prior to treatment and just prior to sacrifice at 14 days following initial treatment. Cerebrospinal fluid (CSF) was collected for polymerase chain reaction (PCR) assay of human DNA. In vitro cell sensitivity to a dose escalation of APAP and cisplatin was assessed in medulloblastoma cell lines DAOY and D238-MED. Results: In vitro viability assays showed that combination APAP plus cisplatin induced synergistic toxicity in human medulloblastoma cells. In saline control rats, the tumor xenograft localized within the cerebellum with spread to the meningeal surfaces and brainstem, and had a volume of 27.1 ±6.7mm3 (mean±SEM). All cisplatin therapy treatment groups showed a significant reduction in final tumor volume when compared to the control group (P < 0.0004). A trend for the cisplatin single therapy group to be less efficacious when compared to the combined cisplatin treatment groups was observed however, the difference was not significant. No reduction in efficacy was seen in the NAC rescue group, with a tumor volume of 4.42±1.36 mm3, compared to 3.30±0.99 mm3 in the APAP plus cisplatin group. Tumor response was not measurable by MR, however the presence of human DNA in the CSF, was correlated with tumor size. Conclusions: This treatment model for medulloblastoma may provide a mechanism to improve chemotherapy efficacy without increasing chemotherapy dose. In vivo and in vitro data correlate to show that the pretreatment with APAP sensitizes cells to cisplatin allowing efficacy at a lower doses, meanwhile delayed treatment with NAC staves off the systemic toxicity normally associated with cisplatin treatments. APAP enhancement with NAC rescue may provide a less toxic option to patients who might otherwise experience systemic toxicity from high doses of cisplatin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3730. doi:1538-7445.AM2012-3730