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ANTICANCER RESEARCH 35: 2479-2486 (2015)

Review Recent Developments in Radiosensitization

JUSTIN LINAM and LI-XI YANG

Department of Radiation Oncology, California Pacific Medical Center, San Francisco, CA, U.S.A.

Abstract. Radiation is essential for local tumor of the present review is to summarize recent developments control for many types of histologies. Technological in radiosensitization, and to identify potential avenues for advancements in recent years have allowed for precise future research. irradiation of target tissues while minimizing the dose to non- target tissues. To enhance radiation damage to cancer cells Hypoxia and further limit the radiation effects on normal tissue, researchers have explored compounds that specifically target Unregulated cell reproduction and growth is the hallmark of cancer cells and make them more sensitive to ionizing many , and as a result of this unregulated growth, radiation. Recent radiosensitization research has focused on tumors can often outgrow their blood supply and thus enter a promising compounds that alter hypoxia, inhibit relatively hypoxic state. Radioresistance due to hypoxia is a topoisomerases, interfere with , and activate well-established problem in cancer treatment. caspases, among other mechanisms. Many such compounds damages tumor DNA in a variety of ways, but an important and have shown impressive results in pre-clinical trials against a often predominant mechanism is the interaction of photons with variety of cell types, but their safety, efficacy and practicability water molecules to create reactive species. These in clinical trials remains to be demonstrated. This review seeks species then damage tumor DNA, which leads to cell apoptosis, to provide an overview of recent research in radiosensitization, necrosis, or inability to divide if unrepaired. Oxygen in the detailing some of the more successful compounds, and microenvironment allows for the perpetuation of free radicals illustrating avenues for future research. and is important in 'fixing' damaged DNA by formation of organic peroxides at damaged sites, which are then resistant to Local control is often of critical importance in the treatment cellular repair mechanisms (1). The importance of oxygen in of cancer. Radiation therapy is an essential tool in achieving the tumor microenvironment is quantified by the oxygen local control for many different types of cancer histology. enhancement ratio (OER) and varies based on the tumor Modern radiation therapeutic technology allows for the histology and on the type of therapeutic radiation (2). delivery of high doses of radiation to a well-defined, The hypoxic state also results in stabilization of a conformal area involved with disease while minimizing the transcription factor known as hypoxia-inducible factor 1 radiation dose to normal, non-target tissue. Despite great (HIF1), which is normally quickly degraded under normoxic technological advancements in radiotherapy, however, the conditions (3). Activation of HIF1 is thought to lead to physics of radiation delivery often necessitate some degree several downstream effects that seem to be associated with of normal tissue irradiation. Compounds that increase cancer higher rates of metastasis and poorer survival, at least in cell sensitivity to radiation ('radiosensitizers') have been some types of cancer (4). used in an effort to optimize radiation therapy. The purpose Because of the adverse radiobiological and clinical consequences of hypoxia, improving tumor oxygenation or otherwise combating the hypoxic tumor microenvironment has been an oncological strategy for over 50 years. Trials of Correspondence to: Li-Xi Yang MD, Ph.D., Radiobiology Laboratory, hyperbaric oxygen were some of the earliest to explore California Pacific Medical Center Research Institute, #602, OPR hypoxic manipulation, and although this intervention improved Bldg, 3801 Sacramento Street, San Francisco, CA 94118, U.S.A. Tel: locoregional control and disease-specific survival, it has not +1 4156006203, e-mail: [email protected] translated into improvements in overall survival based on a Key Words: Radiosensitivity, radiosensitizers,topoisomerase, recent meta-analysis of trials (5). Other radiotherapy, , hypoxia, review. researchers have experimented with Carbogen, a mixture of

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95% oxygen and 5% carbon dioxide, to increase oxygen by catalyzing transient single-strand breaks via formation of concentrations in tumors (6, 7). This strategy is usually used in a phosphotyrosine bond (18). The first topoisomerase conjunction with nicotinamide, which is an inhibitor of poly inhibitor studied was , derived from a closely ADP-ribose polymerase I, an important single-strand break related but inactive compound from the Chinese tree repair enzyme; in models, nicotinamide has been shown to be Camptotheca acuminata (19). Camptothecin and its related a radiosensitizer (8, 9). Despite theoretical promise, however, compounds are thought to cause cytotoxic damage by: (a) results from trials exploring Carbogen with and without stabilizing the topoisomerase/DNA interaction, leading to a nicotinamide have been disappointing (5). Other strategies collision with the DNA replication fork and a subsequent have included administration of tirapazamine, which is a double-strand break (20); (b) terminating RNA synthesis benzotriazine-class molecule that can be reduced to a prematurely (21); and (c) interacting with cell-cycle cytotoxic free- species and can also interact with checkpoints to induce apoptosis (22). Camptothecin and its platinum-based agents in hypoxic cells, derivatives also seem to induce a finite period of resulting in synergistic DNA damage (10). Two phase III trials radiosensitivity distinct from their directly cytotoxic effects, of tirapazamine with radiation and have disappointed: although details about the nature and mechanism of this one showed no survival advantage (11) and the other was radiosensitization remain elusive (19). closed early due to concerns about disproportionate mortality Despite its potent antitumor effects, camptothecin was in the tirapazamine arm (12). found to be too toxic for practical use (23). Other Other manipulations of hypoxia-related pathways are in camptothecin derivatives have been studied, most notably various stages of development. Li and colleagues have recently and . These compounds have antitumor shown that β-elemene, a molecule occurring in Curcuma activity but also have significant toxicity at clinically wenyujin, a traditional Chinese medicine, improved effective doses and are currently approved only for recurrent radiosensitivity of human lung adenocarcinoma cells in mouse or metastatic malignancies, although trials are ongoing (25, models by reducing expression of HIF1α (13). Ning and 26). As some researchers have pointed out, the toxicity of colleagues have shown that dinitroazetidines, a class of these two camptothecin analogs is due to the instability of compounds developed in the aerospace sector, trigger the lactone ring within the molecule (18). Subsequent apoptosis via free radical cascades and have higher stabilization of the lactone ring in a compound known as cytotoxicity than cisplatinum with no appreciable systemic CPT417 revealed topoisomerase inhibition with better tumor toxicity in murine models (14). Although the mechanism of inhibition than topotecan and negligible toxicity in studies of action is not yet understood, these compounds are activated by mammary adenocarcinoma in mice; this compound has the both ionizing radiation and hypoxic conditions, making them advantages of being inexpensively and simply synthesized, attractive agents for combined-modality oncological therapy. and orally bioavailable (18). Clinical trials of CPT417 are Nitroimidazoles have long been known to select for currently underway. hypoxic cells and increase DNA damage caused by ionizing Other camptothecin-related molecules are in preclinical radiation (15). After reduction, these compounds act development. Substitution of hydrophilic moieties at the 7- similarly to oxygen, stabilizing damaged DNA so that it is position of the molecule, the so-called 7-oxyiminomethyl difficult to repair; because oxygen reverses the initial derivatives, have had antitumoric effects against several reduction reaction, these compounds are selectively activated human xenografts (26). Other researchers have substituted a in hypoxic environments (15, 16). This concept was refined difluoromethylene focus in the camptothecin core (BMS- to conceive and then synthesize molecules with two 286309), increasing stability and bioavailability; in vitro and reduction-oxidation loci with different potentials, so-called in vivo experiments comparing this molecule to irinotecan 'bis-bioreductive' molecules (17). Although the utilization of have shown similar antitumoric effects but lower toxicity two nitroimidazoles for this purpose was abandoned due to with BMS-286309 (27). in vivo practicability (17), other researchers have used a combination of a nitroimidazole and a quinone for bis- Manipulation bioreductives (bypassing some of the practical issues with dinitroimidazoles, such as solubility) with good effect, Interfering with microtubule function has been a long- aIthough these studies are in the early stages (16). standing oncological treatment strategy: stabilizing microtubule formation leads to cell-cycle arrest and eventual Topoisomerase Inhibition . Microtubule stabilizers are additionally viewed as radiosensitizers as they often arrest cells in the G2-M stage, Topoisomerase enzymes are essential for human DNA which is the most radiosensitive phase of the (28). replication and transcription. Topoisomerases allow for the are the most developed and widely-used class of unwinding of supercoiled and coiled DNA during replication microtubule stabilizers, but clinical utility is often limited by

2480 Linam and Yang: Recent Developments in Radiosensitization (Review) neurotoxicity, as well as the existence of multidrug-resistance apoptosis in esophageal squamous cell cancer lines, but also genes, enabling tumors to efflux drug, among other resistance seemed to promote the extrinsic apoptotic pathway, based on mechanisms (29). Researchers have explored non- increased levels of tumor necrosis factor-α (36). microtubule stabilizers in an attempt to overcome resistance and achieve a more-favorable toxicity profile. One of the most Targeted-Agents promising of such agents is patupilone (EPO906, B) (28). Patupilone has been shown to overcome resistance Many molecularly targeted-agents have shown great promise with no neurotoxicity in human colonic adenocarcinoma as radiosensitizers, through a variety of pathways. Sorafenib xenografts (28) and has also been shown to be synergistic is an inhibitor of various cell-surface and intracellular with radiation therapy in human medulloblastoma xenografts kinases involved in cellular and tumoral growth, including (30). Another microtubule disrupter that is promising in its kinases of vascular endothelial growth factor pre-clinical results is pyrrolo-1,5-benzoxazepine-15 (PBOX- (VEGF) receptor and platelet-derived growth factor receptor, 15) (31). Rather than stabilizing polymerized microtubules, Rapidly Accelerated Fibrosarcoma (RAF) kinases, and the PBOX family of compounds affect the depolymerization serine/threonine kinases (37). Sorafenib has also been shown of microtubules and initiate apoptotic pathways. Pre-clinical to sensitize hepatocellular carcinoma (HCC) cells to studies on prostate, glioma, and lung cancer cells show that radiation: in a study of four radioresistant HCC cell lines, PBOX-15 remains cytotoxic in tumors with multidrug- sorafenib combined with radiation led to kinase-independent resistance genes, overcomes hypoxic effects, and works enhancement in radiation-induced apoptosis through down- synergistically with ionizing radiation therapy (31). regulation of phospho-Signal transducer and activator of transcription 3 (STAT3), a protein thought to be critical in Second Mitochondria-derived Activator of Caspase HCC progression; radiosensitizing effects were shown in (SMAC) Mimetics vitro and in vivo with HCC xenografts in nude mice (38). The clinical application of sorafenib with radiation in There are two distinct apoptotic pathways based on internal humans has been demonstrated in a study of 31 patients with or external cellular stimulations, but both pathways result in advanced HCC treated with sorafenib and radiotherapy, with the activation of a family of proteases known as caspases. a primary tumor response rate of 100%, with acceptable Damage from chemotherapeutics and ionizing radiation toxicity (39). A phase II trial of radiation therapy and primarily effect the intrinsic pathway (32). In non-apoptotic sorafenib in 40 patients with unresectable HCC showed a states, caspases are regulated by inhibitor of apoptosis less robust but still promising tumor response rate in 55% of proteins (IAPs) (32, 33). When internal cellular signals patients, although there were three treatment-related fatalities initiate the intrinsic apoptotic pathway, however, the (40). Further studies are needed to assess the translational mitochondria release several molecules, including SMAC. benefits of sorafenib as radiation sensitizer. SMAC antagonizes the IAPs, removing caspase inhibition Erlotinib is a small-molecule reversible inhibitor of and allowing the cell to proceed with apoptosis (33). epidermal growth factor receptor (EGFR) tyrosine kinases SMAC-mimetics have been studied as monotherapeutic and has been used against a variety of malignancies, agents against a variety of malignant histological types, but including non-small cell lung cancer, pancreatic cancer, and the resistance of some cell types to SMAC mimetics has led even some non-malignant processes such as to their use in combination with ionizing radiation as myeloproliferative disorders (41). Erlotinib also has a radiosensitizers, such that caspase activation would breadth of radiosensitizing mechanisms, including reduction theoretically be enhanced by the additional pro-apoptotic in fraction of cells in the S-phase of mitosis, inhibiting signaling caused by ionizing radiation (33-36). Tat- expression of radiation response genes such as Rad51, and SMACN7, one such SMAC mimetic, was equally potent at the enhancement of radiation-induced apoptosis by blocking cell killing in vitro and in vivo in both SMAC-resistant and EGFR signaling (42). The clinical applicability of erlotinib SMAC-sensitive esophageal and non-small cell lung cancer as a radiosensitizer has been shown to be very promising in cells (33). Similar studies of SMAC-resistant and SMAC- phase II trials of patients with locally advanced cervical sensitive breast lines were found to be equally cancer (43) and brain metastases from non-small cell lung susceptible to the combination of SM-164 (another SMAC cancer (44), both of which demonstrated excellent response mimetic) and radiation therapy (34); other studies with SM- rates with tolerable toxicity. Cetuximab, a recombinant 164 showed it to be an effective radiosensitizer in head and monoclonal inhibitor of EGFR tyrosine kinase, is neck squamous carcinoma cell lines in xenografts (35). thought to lead to radiosensitivity through mechanisms Studies using LCL161, also a SMAC mimetic, in similar to those of erlotinib and has been studied with combination with radiation found not only that this radiation in patients with head and neck (45), locally compound worked synergistically with irradiation to induce advanced rectal cancer (46), and non-small cell lung cancer

2481 ANTICANCER RESEARCH 35: 2479-2486 (2015)

(47). Although cetuximab with radiation was shown to leading to free radical cascade and oxidative cytotoxicity improve locoregional control of head and neck cancer and (55). The most widely-used have been reduce mortality compared to radiation-alone (45), no -related compounds and derivatives, which are survival advantage was found in patients with lung cancer heterocyclic tetramers of pyrrhole molecules (56). Because when cetuximab was added to concurrent chemoradiation of some disadvantages to first-generation that with (47). Further studies are needed to optimize included suboptimal efficacy as well as inconvenient toxicity the specific contexts and treatment regimens in which profiles, second-generation porphyins were developed, cetuximab has a role. including reduced porphyrins called as well as Other monoclonal have been used as porphyrins with metal ions within the heterocyclic ring radiosensitizers. Bevacizumab, a recombinant antibody against known as (55, 57). Additional porphyrin- the angiogenesis stimulator VEGFA, has been used without related compounds in pre-clinical or clinical stages of radiation for a variety of malignancies, including colorectal, development include synthetic porphyrins called lung, breast, renal, and central nervous system tumors. Recently, porphycenes (58), and pro-porphyrins such as 5- bevacizumab has shown great promise as a radiosensitizing aminolevulinic acids and esters, which are converted into agent in trials of patients with locally advanced cervical cancer porphyrins by endogenous cytosolic enzymes (59). (48) and locally advanced head and neck cancer (49). Although Although photosensitizers in the context of PDT have the mechanism of radiosensitization is incompletely understood, been studied in esophageal (60), lung (60, 61), and other it has been suggested that bevacizumab leads to a somewhat malignancies, PDT is currently reserved as a complementary counterintuitive normalization of chaotic tumor vasculature, therapy or for patients who are not candidates for surgery, allowing for increased perfusion and improved oxygenation in chemotherapy, and radiation. the tumor microenvironment, which in turn enhances radiosensitivity (50). Other Directions Monoclonal antibodies against human epidermal growth factor receptor 2 (HER2), such as trastuzumab, have There are myriad other mechanisms being explored for significantly improved outcomes for patients with breast radiosensitization. Curcumin, an important constituent of the cancer with an overexpression of this cell membrane receptor spice, known as turmeric, has long been known as a (51). These agents may also have a role in the treatment of chemopreventative, but researchers have recently shown that esophageal, gastric, and other malignancies (52). Investigators it is also a potent radiosensitizer of cervical cancer cell lines. have recently shown trastuzumab to have radiosensitizing Although the precise mechanism is unclear, curcumin in activity both alone and synergistically with concomitant combination with ionizing radiation leads to an increase in gefitinib (a small molecule inhibitor of HER2 and other reactive oxygen species, which in turn leads to non-apoptotic EGFRs), seemingly through reduction in radiation-induced cell death via sustained activation of extracellular signal- phosphorylation of EGFR, Methyl ethyl ketone 1/2 (MEK1/2) related kinase-1/-2, at least in some cell types (62). and protein kinase B (Akt), although these pathways are Hydroxychalcones are another type of naturally occurring incompletely understood (53). The activity of trastuzumab as compound present in many types of plant matter; these a radiation sensitizer has been also tested in humans, as a compounds have been shown to have antitumoric as well as prospective trial of 308 patients with non-metastatic breast radiosensitization effects on colonic and pancreatic tumor lines cancer treated with surgery with or without neoadjuvant (63). The mechanism in this case is 'proteotoxicity' via the chemotherapy, followed by adjuvant radiation and trastuzumab hydroxychalcone activation of heat-shock factor 1, resulting (54). In that study, the 4-year locoregional control and overall in heat-shock cascade, and apoptosis (63). Boronic chalcones survival rates were 95% and 98%, respectively, with also have radiosensitizing effects, but their mechanism is acceptable toxicities. More studies of this and other HER- distinct from that of hydroxychalcones. A study of one boronic 2/neu agents are needed to elucidate their radiosensitization chalcone (AM114) in colonic cancer cells showed cytotoxicity mechanism(s) and evaluate their clinical risks and benefits. and radiosensitization that resulted from interference with the 20S subunit of the proteasome, leading to cell death due to the Photosensitizers accumulation of intracellular p53 and p21 (64).

Radiosensitizing compounds have also been used with non- Conclusion ionizing radiation, such as in the 600-800 nm spectrum of wavelengths, to treat cancer as a modality known as Radiation therapy is essential in local control of many, if not photodynamic therapy (PDT). These ‘photosensitizers’ most, cancer histologies. Technological advances such as absorb photons of a certain wavelength and enter an excited computed tomography-based planning, intensity-modulated state that can interact with O2 to produce , radiation therapy, image-guided radiation therapy, and

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