Abstract C129: Darinaparsin sensitizes solid tumors but not normal tissues to radiation.
Authors: Tian Junqiang , Zhao Hongjuan , Nolley Rosalie , Reese Stephen , Li Xuejun , Peehl Donna , Knox Susan 
Published: June 2012

Background: Darinaparsin (DPS; provided by ZIOPHARM Oncology, Inc.) is a novel organic arsenical (dimethylated arsenic linked to glutathione) with promising anticancer activity and a favorable systemic toxicity profile. We have found that DPS sensitizes solid tumor cells to radiation under hypoxia with much higher potency than arsenic trioxide (ATO). This in vitro radiosensitizing effect occurs at a concentration well below the peak blood concentrations achieved in humans and dogs at relative safe doses of DPS. Therefore, we performed experiments to assess the in vivo radiosensitizing effect of DPS in mouse models of subcutaneous xenograft tumors with different radiation dosing regimens. In addition, we studied the potential radiosensitizing effect of DPS on normal radiosensitive intestine and bone marrow.

Materials and Methods: Human prostatic [hormone-independent (HI) LAPC-4] and pancreatic [PANC-1] cancer cells were implanted subcutaneously in nude mice. When the tumors reached ∼200 mm∘3, the mice were treated with DPS (100 mg/kg, IP) or saline as a control, followed 4 hrs later by local tumor x-ray irradiation. Intestinal crypt microcolony assay and blood cell counts were used to assess the effect of DPS on intestinal and bone marrow cell radiosensitivity, respectively.

Results: In both HI-LAPC-4 and PANC-1 tumor models, a single dose of DPS 4 hrs before radiation (5 Gy) significantly enhanced radiation-induced tumor growth inhibition, with an increase in the tumor doubling time from 9.7 days (95% CI: 9.5 − 10) to 15 days (95% CI: 14.5 − 15.5) in HI-LAPC-4 tumors (P &lt; 0.0001), and 11 days (95% CI: 10.3 − 12.0) to 18 days (95% CI: 16.1 − 20.3) in PANC-1 tumors (P &lt; 0.0001). We also tested the effect of DPS in combination with a clinically-relevant fractionated radiation regimen (2 Gy/day × 3 consecutive days) using the HI-LAPC-4 tumor model. A significant delay of tumor volume doubling time was observed from 8.4 days with radiation alone (95% CI: 8.1 − 8.5) and 6.2 days with DPS alone (95% CI: 6.0 − 6.5) to 14.7 days for the combined treatment of radiation and DPS (95% CI: 14 − 15.6) (P &lt; 0.0001). In contrast, a similar regimen of combined treatment of DPS (100 mg/kg, IP) and radiation (3.5 Gy, 4 hr after DPS) did not have a radiosensitizing effect on bone marrow hematopoietic activity, as measured by the WBC, neutrophil, platelet, and RBC counts. Furthermore, DPS (100 mg/kg, IP) 4 hr before radiation (10–15 Gy) significantly protected the radiation-induced loss of viable crypts as assessed by the in vivo crypt cell microcolony assay.

Conclusions: DPS has significant in vivo radiosensitizing effects against prostatic and pancreatic cancer tumors in vivo in xenograft tumor models. DPS-mediated radiosensitization was observed in prostate tumors with both single and fractionated irradiation dosing regimens. Importantly, we did not observe any systemic toxicity with the DPS treatment alone, or any DPS-induced radiosensitization in normal radiosensitive tissues. These results suggest that DPS has the potential to radiosensitize relatively radioresistant tumors without sensitizing normal tissues, and thereby increase the therapeutic index of radiation therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C129.