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DNA repair processes are critical for cellular survival and for maintenance of genomic stability. Radiation therapy and various chemotherapeutic agents can kill cancer cells by inducing DNA damage. The persistence of even a single unrepaired DNA doublestrand break is lethal to the cell; therefore, repair processes and stress response signaling pathways are involved in the recovery from such damage. Predominant mechanisms that are activated in response to ionizing radiation (IR) induced DNA damage include non-homologous end joining (NHEJ) and homologous repair (HR). However, other processes important for cellular genome maintenance include mismatch repair (MMR) and base excision repair (BER). Mutations in the component proteins of repair complexes underlie both mechanisms of cellular radiation sensitivity and carcinogenesis.
Human cancers are postulated to arise after accumulation of multiple random mutations and epigenetic modifications that select for tumor progression. These mutations and epigenetic changes may also lead to individual differences in tumor responses to radiation sensitizers and to therapy induced DNA damage (Fig. 1A). Thus, radiation sensitizers that target specific sets of tumor modifications may be selectively lethal to cancer cells.
We apply here the radiobiological definition of radiation sensitivity, as defined by an increased steepness of the terminal slope of the cellular radiation survival curve. The larger the radiation dose, the greater is the separation from the control clonogenic radiation survival curve (Fig. 1B). However, as a category, such radiation sensitizing drugs have not met expectations. Other drugs, with properties suitable for augmenting radiation induced cell killing at low to modest radiation doses by decreasing the “shoulder” regions of survival curves, have demonstrated greater clinical utility. Such agents as the DNA intercalating agents (cis-platinum), the molecular targeted growth receptor regulated pathways (EFGR pathway inhibitors) and the anti-metabolite, 5-fluorouracil (5-FU) are frequently used in conjunction with conventional radiation fractionation. Pro-drugs have been developed, requiring cellular uptake and metabolism to the active chemical form, offering practical advantages in drug delivery and improving local disease control when combined with radiation. Diseases showing clinical benefit from chemoradiosensitization have included cancers of the GI, GU and Gyn systems. Radiation sensitizers for use with hypo-fractionated radiation therapy remain to be developed.
Targeting molecules in DNA damage repair pathways and developing improved tumor imaging and radiation delivery technology offer additional promise for clinical translation. Traditional large field radiation therapy (RT) techniques that encompass the tumor with generous margins represent a paradigm that is undergoing refinement by applying conformal radiation treatment planning and delivery. Tumors diagnosed earlier in the disease course, staged more precisely and treated with focused RT are now subjected to larger fractions of RT offering radiobiological benefits and improved local control.5,6
Human tumors may also vary in the expression of proteins required for repair processes. DNA repair pathways, including the MMR and BER pathways, are important in determining the ability of anti-metabolites to act as radiation sensitizers. This is important, as epigenetic silencing of MMR genes may contribute to the development of up to 15% of sporadic cancers.7 Studies have shown that MMR deficiency may increase anti-metabolite radiation sensitization by increasing anti-metabolite incorporation into the DNA.8
In this issue of Cancer Biology and Therapy, Aziz and colleagues show that the activity of the BER protein MED1/MBD4 is modulated by its N-terminal methyl binding domain while acting on iododeoxyuridine (IUdR) generated mispairs.9 MED1/MBD4, a DNA N-glycosylase, preserves genomic integrity by correcting mismatches that occur at CpG methylation sites.10 In addition, MED1/MBD4 exhibits glycosylase activity on several therapy induced substrates, including 5-FU, suggesting that MED1/MBD4 may be involved in resistance to other anti-metabolites.11 MED1 is frequently mutated in MMR-deficient tumors displaying micro-satellite instability leading to a truncated MED1/MBD4 protein lacking N-glycosylase activity.12-14 It has been proposed that the truncated protein acts in a dominant negative manner by binding modified DNA sites and preventing the binding of wild type MED1/MBD4.15
These authors demonstrate that the N-terminal domain of MED1 can inhibit full-length MED1. This finding predicts that MED1-deficient tumors, such as those expressing the truncated mutant, may benefit from anti-metabolite sensitization in a different manner than observed for “wild type” tumors.15
Such findings also raise interesting issues for potential application of personalized radiation sensitizing cancer therapy. Given our current understanding of the DNA repair pathways (Fig. 1A), in principal, it is possible to design novel cancer treatments to directly target individual human cancers. The DNA damage response (DDR) pathway promotes cell cycle arrest via the ATM pathway and double stand break repair by NHEJ and HR. BRCA1 and BRCA2, important components of the DDR pathway that are commonly mutated in human breast cancers, participate in HR. HR-deficient tumors are sensitive to stalled replication forks. Radiation sensitizers that induce stalled replication forks, such as mitomycin C and cisplatin, may be more effective in BRCA1/2 deficient tumors.16 This hypothesis remains to be tested in the limited number of patients with tumors with these defects.
However, there may be further interest in true radiation sensitizers, based on technological advances. Improvements in the precision of radiation dose delivery and tumor localization/tracking have lead to progressively conformal radiation therapy. This has allowed for the sparing of adjacent normal tissue and the use of hypofractionation (abbreviated treatment courses with radiation fractions of > 4 Gy). These hypofractionated regimens allow for the delivery of higher biologically equivalent radiation doses and may be more effective for the treatment of slow growing tumors such as prostate cancer.17
At doses greater than 4 Gy, the importance of DNA repair pathways are marginalized as the shoulder on the cell survival cure is surpassed (Fig. 1B). As abbreviated hypofractionation treatment regimens become more common in the future, the role of radiosensitization and the optimal radiosensitizers must be re-evaluated.
Recent approaches to radiation sensitization have moved away from manipulation of DNA repair pathways to modifications of cell survival pathways. Cell survival following radiation therapy is a complex process that may be adversely impacted by apoptosis and senescence. Signal transduction pathways important in promoting cell survival include the RAS, RAF, NFκB, STAT and PI3K mediated pathways. Individual pathway activations vary in tumors and drugs that modify these pathways, which in theory, may promote tumor cell death in response to radiation in a patient specific manner. Accurate biomarkers for predicting individual tumor responses to such inhibitors are needed.18
Epigenetic changes also play important roles in the development of cancers by effecting differentiation and apoptotic pathways. Specifically, modifications of histone lysines by acetylation and deacetylation effect the expression of genes integral to tumor progression. Histone deacetylase (HDAC) inhibitors have been shown to be potent radiation sensitizers. They may also offer further enhancement of the therapeutic index by protecting adjacent normal tissues,19 an important consideration in hypofractionated radiation therapy. Future work will define the subset of isoforms that are overexpressed in individual tumors and those that are targets for radiation sensitization.
The goal of radiation sensitization is to maximize tumor responses while minimizing normal tissue toxicity. Currently, clinical experience allows us to choose radiation sensitizers for a given type of tumor for use with standard radiation fractionation. Current research focuses on defining the pathways of radiation resistance, so more individualized radiation fractionation schemes and sensitizers can be developed. We look toward integrating the new, -omic technologies to afford us the opportunity to define the tumor genomic make-up and predict its response to radiation. We should prepare to incorporate such information into personalized patient care.
Aziz MA, Schupp JE, Kinsella TJ Modulation of the activity of methyl binding domain protein 4 (MBD4/MED1) while processing iododeoxyuridine generated DNA mispairs Cancer Biol Ther 2009 8 1156 63 doi: 10.4161/cbt.8.12.8536.
Previously published online: www.landesbioscience.com/journals/cbt/article/8750