ZIOPHARM Oncology, Inc. (Nasdaq: ZIOP), a drug development company employing small molecule and synthetic biology approaches to cancer therapy, announced today new preclinical data from two separate studies of darinaparsin (Zinapar® or ZIO-101), a novel organic arsenic, in various solid tumor models at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, taking place November 12-16 in San Francisco. Both studies were conducted at the Stanford University School of Medicine by lead author, Junqiang Tian, M.D., Ph.D., senior author, Susan J. Knox, M.D., Ph.D., from the Department of Radiation Oncology, and were performed in collaboration with co-author, Donna Peehl, Ph.D., Professor of Urology.
In the first study, titled "Darinaparsin sensitizes solid tumors but not normal tissues to radiation," human prostatic [hormone-independent (HI) LAPC-4] and pancreatic [PANC-1] tumor models were treated with darinaparsin (100 mg/kg) or saline (control), with the addition of local tumor x-ray irradiation. Previous preclinical work at Stanford established darinaparsin's cytotoxic and radiation enhancing modes of action under both normoxic (NO) and hypoxic (HO) conditions in prostate cancer, pancreatic cancer, cervical cancer, and glioblastoma cell lines. Hypoxia is an important condition in the microenvironment of solid tumor cells which creates resistance to cytotoxic drugs and radiation and causes cancer stem cells to re-grow the tumor. This study was performed to assess the effect of different radiation dosing regimens as well as the potential radiosensitizing effect of darinaparsin on normal radiosensitive intestine and bone marrow.
Intestinal crypt microcolony assay and blood cell counts were used to assess the effect of darinaparsin on intestinal and bone marrow cell radiosensitivity, respectively. In both the prostate and pancreatic tumor models, a single dose of darinaparsin four hours before radiation significantly enhanced radiation-induced tumor growth inhibition, with a significant delay of tumor volume doubling time observed from 8.4 days with radiation alone and 6.2 days with darinaparsin alone, to 14.7 days for the combined treatment of radiation and darinaparsin. Darinaparsin-mediated radiosensitization was observed in prostate tumors with both single and fractionated irradiation dosing regimens. Importantly, no systemic toxicity was observed with the darinaparsin treatment alone, and darinaparsin did not sensitize normal intestinal epithelium and bone marrow to the effect of radiation at the studied dose.
"These results suggest that darinaparsin has the potential to sensitize relatively radioresistant tumors without affecting normal tissues," commented senior author, Susan J. Knox. "They further suggest that darinaparsin may increase the therapeutic index of radiation therapy and, as was shown with our first study, have near-term translational potential."
A second study, titled "Darinaparsin is an anti-solid tumor cytotoxin in vivo," again evaluated prostate and pancreatic tumor models treated with darinaparsin (100 mg/kg) or saline (control). In both the prostate and pancreatic tumor models, darinaparsin significantly inhibited tumor growth (p < 0.0001), with the average tumor volume doubling time increasing from 3.95 days to 11.8 days in the prostate tumor model, and 3.83 days to 6.82 days in the pancreatic tumor model. Importantly, no significant systemic toxicities were exhibited at studied dose, as assessed by organ histology and blood biochemistry.
Dr. Knox remarked: "Darinaparsin was found to have significant cytotoxic activity in these two well-established solid tumor models, without apparent systemic toxicity. With darinaparsin currently in clinical development, these findings may have near-term translational potential."
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