Blocking Cyclin-Dependent Kinase 4/6 During Single Dose Versus Fractionated Radiation Therapy Leads to Opposite Effects on Acute Gastrointestinal Toxicity in Mice

Abstract

The delivery of radiation therapy to cure gastrointestinal (GI) cancers is often limited by normal tissue toxicity of the GI tract. Studies using genetically engineered mice have demonstrated an essential role of the cyclin-dependent kinase inhibitor p21 in protecting against GI acute radiation syndrome (GI-ARS). Here, we examined the impact of the Food and Drug Administration-approved, selective, cyclin-dependent kinase 4/6 inhibitor palbociclib (PD-0332991) on the development of GI-ARS induced by single-dose versus fractionated radiation in mice. For the single-dose radiation study, C57BL/6J mice were treated with palbociclib or vehicle 28 and 4hours before subtotal body irradiation (SBI). For the fractionated radiation study, C57BL/6J mice were exposed to fractionated SBI for 5 consecutive days. These mice were treated with palbociclib or vehicle either 28 and 4hours before the first dose of irradiation or 4hours before the first, third, and fifth doses of irradiation. Our data indicate that treatment with palbociclib before, but not after, a single fraction of SBI significantly ameliorated GI-ARS, improved the integrity of the GI barrier, and increased the number of surviving crypts in the small intestine. In addition, palbociclib did not protect tumor cell lines from radiation invitro. In contrast to the results from the single-dose exposure, treatment with palbociclib before 5 daily fractions of SBI did not prevent GI-ARS. Moreover, we unexpectedly observed that GI-ARS was exacerbated in mice treated with palbociclib before and during 5 daily fractions of SBI. Our results demonstrate that treatment with palbociclib before a single dose of SBI protects mice from GI-ARS. In contrast, treatment with palbociclib before and during 5 daily fractions of SBI exacerbates GI-ARS in mice. These results emphasize the importance of conducting preclinical studies of radioprotectors with single-dose and fractionated radiation therapy.