Kenneth A. Jenrow

Mechanisms of radiation-induced normal tissue toxicity and implications for future clinical trials

To summarize current knowledge regarding mechanisms of radiation-induced normal tissue injury and medical countermeasures available to reduce its severity. Advances in radiation delivery using megavoltage and intensity-modulated radiation therapy have permitted delivery of higher doses of radiation to well-defined tumor target tissues. Injury to critical normal tissues and organs, however, poses substantial risks in the curative treatment of cancers, especially when radiation is administered in combination with chemotherapy. The principal pathogenesis is initiated by depletion of tissue stem cells and progenitor cells and damage to vascular endothelial microvessels. Emerging concepts of radiation-induced normal tissue toxicity suggest that the recovery and repopulation of stromal stem cells remain chronically impaired by long-lived free radicals, reactive oxygen species, and pro-inflammatory cytokines/chemokines resulting in progressive damage after radiation exposure. Better understanding the mechanisms mediating interactions among excessive generation of reactive oxygen species, production of pro-inflammatory cytokines and activated macrophages, and role of bone marrow-derived progenitor and stem cells may provide novel insight on the pathogenesis of radiation-induced injury of tissues. Further understanding the molecular signaling pathways of cytokines and chemokines would reveal novel targets for protecting or mitigating radiation injury of tissues and organs.

Modification of radiation injury by ramipril, inhibitor of angiotensin-converting enzyme, on optic neuropathy in the rat

Abstract Kim, J. H., Brown, S. L., Kolozsvary, A., Jenrow, K. A., Ryu, S., Rosenblum, M. L. and Carretero, O. A. Modification of Radiation Injury by Ramipril, Inhibitor of Angiotensin-Converting Enzyme, on Optic Neuropathy in the Rat. Radiat. Res. 161, 137–142 (2004). Inhibitors of angiotensin-converting enzyme (ACE) have been used to reduce radiation-induced normal tissue injury. The present study was carried out to determine whether ramipril, one of the inhibitors of ACE, would ameliorate radiation-induced brain damage, using a well-characterized optic neuropathy model in the rat, one of the most critical and radiosensitive structures in the brain. The brains of adult Fischer rats were irradiated stereotactically with 30 Gy using a single collimated beam. Six months after irradiation and 1.5 mg/kg day−1 ramipril (started 2 weeks after irradiation), rats were assessed for optic nerve damage functionally, using visual evoked potential, and histologically. Results show that ramipril conferred significant modification of radiation injury, since rats receiving radiation alone showed a threefold lengthening in the mean peak latency in the visual evoked potential, whereas 75% of rats receiving radiation followed by ramipril had evoked potentials that resembled those of normal untreated control rats. The histology of irradiated and ramipril-treated optic nerves appeared nearly normal, while there was significant demyelination in both optic nerves of irradiated rats. The study represents the first demonstration of prophylaxis of radiation injury by a carboxyl-containing ACE inhibitor, providing a pharmacological strategy designed to reduce radiation-induced normal tissue damage.

Selective inhibition of microglia-mediated neuroinflammation mitigates radiation-induced cognitive impairment

Cognitive impairment precipitated by irradiation of normal brain tissue is commonly associated with radiation therapy for treatment of brain cancer, and typically manifests more than 6 months after radiation exposure. The risks of cognitive impairment are of particular concern for an increasing number of long-term cancer survivors. There is presently no effective means of preventing or mitigating this debilitating condition. Neuroinflammation mediated by activated microglial cytokines has been implicated in the pathogenesis of radiation-induced cognitive impairment in animal models, including the disruption of neurogenesis and activity-induced gene expression in the hippocampus. These pathologies evolve rapidly and are associated with relatively subtle cognitive impairment at 2 months postirradiation. However, recent reports suggest that more profound cognitive impairment develops at later post-irradiation time points, perhaps reflecting a gradual loss of responsiveness within the hippocampus by the disruption of neurogenesis. We hypothesized that inhibiting neuroinflammation using MW01-2-151SRM (MW-151), a selective inhibitor of proinflammatory cytokine production, might mitigate these deleterious radiation effects by preserving/restoring hippocampal neurogenesis. MW-151 therapy was initiated 24 h after 10 Gy whole-brain irradiation (WBI) administered as a single fraction and maintained for 28 days thereafter. Proinflammatory activated microglia in the dentate gyrus were assayed at 2 and 9 months post-WBI. Cell proliferation and neurogenesis in the dentate gyrus were assayed at 2 months post-WBI, whereas novel object recognition and long-term potentiation were assayed at 6 and 9 months post-WBI, respectively. MW-151 mitigated radiation-induced neuroinflammation at both early and late time points post-WBI, selectively mitigated the deleterious effects of irradiation on hippocampal neurogenesis, and potently mitigated radiation-induced deficits of novel object recognition consolidation and of long-term potentiation induction and maintenance. Our results suggest that transient administration of MW-151 is sufficient to partially preserve/restore neurogenesis within the subgranular zone and to maintain the functional integrity of the dentate gyrus long after MW-151 therapy withdrawal.

Antioxidant Diet Supplementation Starting 24 Hours after Exposure Reduces Radiation Lethality

Abstract Antioxidants mitigate radiation-induced lethality when started soon after radiation exposure, a delivery time that may not be practical due to difficulties in distribution and because the oral administration of such agents may require a delay beyond the prodromal stage of the radiation syndrome. We report the unexpected finding that antioxidant supplementation starting 24 h after total-body irradiation resulted in better survival than antioxidant supplementation started soon after the irradiation. The antioxidant dietary supplement was l-selenomethionine, sodium ascorbate, N-acetyl cysteine, α-lipoic acid, α-tocopherol succinate, and co-enzyme Q10. Total-body irradiation with 8 Gy in the absence of antioxidant supplementation was lethal by day 16. When antioxidant supplementation was started soon after irradiation, four of 14 mice survived. In contrast, 14 of 18 mice receiving antioxidant supplementation starting 24 h after irradiation were alive and well 30 days later. The numbers of spleen colonies and blood cells were higher in mice receiving antioxidant supplementation starting 24 h after irradiation than in mice receiving radiation alone. A diet supplemented with antioxidants administered starting 24 h after total-body irradiation improved bone marrow cell survival and mitigated lethality, with a radiation protection factor of approximately 1.18.

Plerixafor, a CXCR4 Antagonist, Mitigates Skin Radiation-Induced Injury in Mice

Even with modern 3D conformal treatments skin radiation injury can be an inadvertent complication associated with clinical radiotherapy particularly at tissue folds. It is also of concern in the context of a radiological terrorism incident or accident, since skin irradiation lowers the lethal dose of whole body radiation. We hypothesize that radiation-induced skin injury originates from a loss of stem and progenitor cells, accompanied by excessive ROS production and proinflammatory cytokines. Plerixafor, a CXCR-4 antagonist, is one of the most efficient bone marrow stem cell mobilizers and these studies were designed to experimentally assess the potential of Plerixafor to reduce skin radiation injury. The right hind legs of groups of C57BL/6 mice were exposed to radiation alone or in combination with Plerixafor. Plerixafor was administered intraperitoneally at a dose of 5 mg/kg given in two doses separated by two days and started either on day 0, 4, 7, 15 or 24 after irradiation. The primary end point was skin injury, which was assessed three times a week for at least 2 months using a semi-quantitative scale. Secondary end points measured at selected time points included histology (primarily H&E) and cytokine levels (TGF-β and TNF-α). The acute and late skin injury in mice receiving Plerixafor was highly dependent on the timing of administration of the drug. The maximum benefit was observed when the drug was started 1 week after radiation exposure, and earlier or later administration of the drug decreased its efficacy. Secondary damage end points (cytokine levels and histologically assessed tissue thickness) provided confirmatory observations. In an attempt to gain insight into the effect of timing of administration of the agent on the mitigation effect, the ligand to CXCR4, stromal derived factor, SDF-1, was measured as a function of time after radiation exposure. Expression of SDF-1 monitored in skin as a function of time after a 30 Gy radiation exposure suggested a strong correlation between timing of administration of Plerixafor and expression of SDF-1 in irradiated skin: optimum drug administration timing coincided with maximal SDF-1 expression in the skin of irradiated mice. This report presents the first observation that CXCR4 antagonist improves both acute and late skin response to radiation exposure.

Novel biological strategies to enhance the radiation therapeutic ratio

Successful anticancer strategies require a differential response between tumor and normal tissue (i.e., a therapeutic ratio). In fact, improving the effectiveness of a cancer therapeutic is of no clinical value in the absence of a significant increase in the differential response between tumor and normal tissue. Although radiation dose escalation with the use of intensity modulated radiation therapy has permitted the maximum tolerable dose for most locally advanced cancers, improvements in tumor control without damaging normal adjacent tissues are needed. As a means of increasing the therapeutic ratio, several new approaches are under development. Drugs targeting signal transduction pathways in cancer progression and more recently, immunotherapeutics targeting specific immune cell subsets have entered the clinic with promising early results. Radiobiological research is underway to address pressing questions as to the dose per fraction, irradiated tumor volume and time sequence of the drug administration. To exploit these exciting novel strategies, a better understanding is needed of the cellular and molecular pathways responsible for both cancer and normal tissue and organ response, including the role of radiation-induced accelerated senescence. This review will highlight the current understanding of promising biologically targeted therapies to enhance the radiation therapeutic ratio.