Abstract
Unresectable pancreatic cancer is almost universally lethal because chemotherapy and radiation cannot completely stop the growth of the cancer. The major problem with using radiation to approximate surgery in unresectable disease is that the radiation dose required to ablate pancreatic cancer exceeds the tolerance of the nearby duodenum. WR-2721, also known as amifostine, is a well-known radioprotector, but has significant clinical toxicities when given systemically. WR-2721 is a prodrug and is converted to its active metabolite, WR-1065, by alkaline phosphatases in normal tissues. The small intestine is highly enriched in these activating enzymes, and thus we reasoned that oral administration of WR-2721 just before radiation would result in localized production of the radioprotective WR-1065 in the small intestine, providing protective benefits without the significant systemic side effects. Here, we show that oral WR-2721 is as effective as intraperitoneal WR-2721 in promoting survival of intestinal crypt clonogens after morbid irradiation. Furthermore, oral WR-2721 confers full radioprotection and survival after lethal upper abdominal irradiation of 12.5 Gy × 5 fractions (total of 62.5 Gy, EQD2 = 140.6 Gy). This radioprotection enables ablative radiation therapy in a mouse model of pancreatic cancer and nearly triples the median survival compared to controls. We find that the efficacy of oral WR-2721 stems from its selective accumulation in the intestine, but not in tumors or other normal tissues, as determined by in vivo mass spectrometry analysis. Thus, we demonstrate that oral WR-2721 is a well-tolerated, and quantitatively selective, radioprotector of the intestinal tract that is capable of enabling clinically relevant ablative doses of radiation to the upper abdomen without unacceptable gastrointestinal toxicity.
Highlights
For patients with unresectable pancreatic cancer, there are no effective treatments that protect the GI tract from this radiotoxicity, and ablative radiotherapy is not currently possible
Systemic dosing of WR-2721 by intraperitoneal (IP) injection has already been shown to be effective at radioprotecting the gut of C3Hf/KamLaw mice receiving whole body irradiation[11,12], but we wanted to determine if oral (PO) administration of WR-2721 would be efficacious
We tested a range of doses of oral WR-2721 from 0 to 1,000 mg/kg, followed either 15 or 30 minutes after by a morbid dose of whole body irradiation (WBI)
Summary
For patients with unresectable pancreatic cancer, there are no effective treatments that protect the GI tract from this radiotoxicity, and ablative radiotherapy is not currently possible. WR-2721 is a prodrug that is hydrolyzed by alkaline phosphatases that are enriched in normal tissues[6] to the active cytoprotective free thiol metabolite, WR-10657. We reasoned that a dose of WR-2721 given orally just before radiation could be rapidly activated by the endogenous digestive enzymes in the duodenum and jejunum to its active WR-1065 metabolite This enterally-activated form of WR-2721 would accumulate in high concentrations in the intestines and provide localized radioprotection with potentially fewer systemic side effects. This could be useful during radiation for pancreatic cancer, since the duodenum and jejunum are dose-limiting organs preventing ablative radiation treatments. We demonstrate that the drug is well–tolerated and accumulates its active metabolite, WR-1065 in significantly higher levels in the GI tract compared to the plasma, liver or even spontaneous pancreatic tumors
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