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REVIEW ARTICLE
Year : 2009  |  Volume : 5  |  Issue : 9  |  Page : 16-20

Enhancement of radiation and chemotherapeutic drug responses by 2-deoxy-D-glucose in animal tumors


1 Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, New Delhi, India; Department of Radiation Oncology, Sylvester Comprehensive Cancer Centre University of Miami, FL/USA
2 Division of Radiation Biosciences, Institute of Nuclear Medicine and Allied Sciences, New Delhi, India

Date of Web Publication21-Aug-2009

Correspondence Address:
B S Dwarakanath
Institute of Nuclear Medicine and Allied Sciences, New Delhi - 110 054, India

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.55135

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 > Abstract 

The development of an approach based on the energy-linked modification of DNA repair and cellular recovery processes using 2-deoxy-D-glucose (2-DG; inhibitor of glycolytic ATP production) has shown promising results in a number of model systems of cancer. Following encouraging results on the tolerance and toxicity (acute as well as late effects) of the combination (2-DG and hypofractionated radiotherapy) in Phase I and II clinical trials, its efficacy is currently under evaluation in Phase III clinical trials for glioma patients. Since heterogeneous physiologic and metabolic status in tumors as well as host-tumor interactions influence the local tumor control, which coupled with systemic disturbances could determine the cure (long-term tumor free survival), investigations on the in vivo responses of tumors to the combined treatment have received considerable attention. This communication provides a brief overview on the in vivo studies related to radio- and chemosensitization of tumors by 2-DG, besides the normal tissue toxicity induced by the combined treatment of 2-DG and radiation or chemotherapeutic drugs.

Keywords: Animal tumors, chemotherapeutic drugs, immunomodulation, normal tissue toxicity, radiation, 2-deoxy-D-glucose


How to cite this article:
Gupta S, Farooque A, Adhikari J S, Singh S, Dwarakanath B S. Enhancement of radiation and chemotherapeutic drug responses by 2-deoxy-D-glucose in animal tumors. J Can Res Ther 2009;5, Suppl S1:16-20

How to cite this URL:
Gupta S, Farooque A, Adhikari J S, Singh S, Dwarakanath B S. Enhancement of radiation and chemotherapeutic drug responses by 2-deoxy-D-glucose in animal tumors. J Can Res Ther [serial online] 2009 [cited 2019 Jul 18];5:16-20. Available from: http://www.cancerjournal.net/text.asp?2009/5/9/16/55135


 > Introduction Top


The presence of anaerobically metabolizing, radioresistant, and repair proficient hypoxic cancer cells as well as normal tissue tolerance is one of the limitations of conventional treatment modalities for cancer. Poorly differentiated and rapidly growing malignant tumors are generally characterized by higher rates of glucose usage and glycolysis as compared to corresponding normal tissues. [1],[2]

An increase in glucose uptake is the earliest change observed in cells after malignant transformation.[3],[4] Enhanced glucose uptake and glycolysis in tumors arise due to multiple reasons including oncogenic transformation-linked alterations in gene expressions, mitochondrial mutations and hypoxia in the case of solid tumors that result in enhanced levels and activities of glucose transporters and glycolytic enzymes. [5],[6],[7] A strong correlation between glucose uptake, glycolysis, hypoxia, and treatment resistance in tumors has important implications in the management of cancer patients, where the distinguishing anaerobic environment of tumor cells leading to their dependence on glycolysis can be exploited for obtaining a therapeutic gain. The glucose antimetabolite, 2-DG, a competitive inhibitor of glucose transport and glucose phosphorylation by hexokinase, is known to selectively inhibit glycolytic energy (adenosine triphosphate [ATP]) production [8],[9],[10] and therefore energy-dependent DNA repair and cellular recovery processes in monolayer cultures of human tumor cell lines. [11],[12],[13]

Following the observations of inhibition in cell proliferation and stimulation of cell death by 2-DG in murine and human tumor cell lines, several studies have examined the effects of 2-DG as a primary therapeutic agent in providing local tumor control in a number of murine and rodent tumor models [14],[15],[16],[17] as well as xenografted human tumors. [18] 2-DG was shown to inhibit tumor growth in animal models if given continuously for several days. [14] Initial attempts to treat cancer patients with 2-DG as an anticancer agent proved unsuccessful and were abandoned, [19] since continuous administration of 2-DG at higher doses (required for therapeutic effects) for long time could be toxic. Subsequently, 2-DG was utilized as an adjuvant to radiation and encouraging results were obtained both in vitro , [10],[20] in multicellular spheroids, [21] and in vivo . [22],[23] These results led to the clinical trials in malignant glioma patients, where excellent tolerance to the combined treatment of 2-DG with hypofractionated radiotherapy has been observed with minimal acute toxicity as well as late radiation damage [24],[25] and enhanced quality of life. Therapeutic efficacy of this treatment regimen is currently under evaluation in Phase III clinical trials.


 > Modification of Radiation Response by 2-DG Top


The adverse effects on normal tissue due to radiotherapy (RT) administration as well as chemoresistance are possible causes of the poor response to treatment in advanced stage tumors and therefore, the development of new combination of agents is a promising area of research. In addition, normal tissue tolerance has limited radiation dose escalation and has also resulted in an inability to combine this treatment with full dose chemotherapy. 2-DG has shown promising results as an adjuvant of radiation therapy and chemotherapy both in vitro and in vivo.

Jain et al. envisaged that 2-DG can be used as an adjuvant rather than a therapeutic agent. [11] Several studies beginning from 1977 showed that indeed 2-DG can be used as a modulator of radiation response. The administration of 2-DG just before the focal irradiation of the tumor has been found to elicit complete response (total tumor regression and cure) in Ehrlich ascites tumor (EAT)-bearing mice in a dose-dependent manner, with nearly 50% cure rates at a dose of 2 g/kg body weight. [11],[23],[26] However, a considerable amount of variation in the degree of radiosensitization by 2-DG has been observed among different animal tumors. [11],[26]

The temporal sequence of molecular events involved in cellular responses to external beam ionizing radiation is rather clearly defined with the initiation of various processes starting soon after irradiation that lasts for few to several minutes. Therefore, the optimization of protocols designed using 2-DG, that alter signal transduction processes related to damage response pathways (prosurvival and prodeath; both mitotic and apoptotic) appear to be critical in providing a better local tumor control. Indeed, preclinical studies using a combination of intravenously administered 2-DG, 5-10min before focal irradiation of the tumor with either gamma rays [11],[23],[27] or proton beams [28] have shown excellent results where cure (tumor-free survival) rates of 50-60% have been achieved under certain conditions. This perhaps is one of the reasons why a significant improvement in the local control has not been observed in some of the studies either with radiation or chemotherapeutic drugs [15],[29],[30] although variations in biological behavior of the tumor cells as well as physiological status could also contribute to this heterogeneous response. In this context, it is noteworthy that a preclinical study reported a reduction in the efficacy of radioimmunotherapy (RIT) by 2-DG, [31] which could be partly due to the inability in achieving an optimal treatment regimen as induction of lesions is spread over a long time interval and overlaps with the damage response events. Future efforts should focus on optimizing the treatment protocol, particularly regarding the timing of administration of 2-DG with reference to tumor irradiation or administration of chemotherapeutic drugs.


 > Modification of Chemotherapeutic Drug Responses by 2-DG Top


Since cellular responses to damage caused by many anticancer drugs are similar to responses to radiation, 2-DG has also been investigated as an adjuvant in the cancer chemotherapy. In vitro studies with different tumor cell lines and chemotherapeutic drugs have indeed shown enhanced cell death by the combination. [32],[33] Since most of the chemotherapeutic drugs target the rapidly dividing cells leaving the slow-growing hypoxic tumor cells, the use of 2-DG with these drugs should selectively target these tumor cells without affecting the normally oxygenated cells. Recent studies have indeed shown that the administration of 2-DG following chemotherapeutic drugs like etoposide, doxorubicin, and paclitaxel induced either partial or complete responses, depending on the 2-DG dose and tumor type. [29],[30]

The administration of 2-DG, 4 h after etoposide injection enhanced the growth delay of EAT and Dalton's lymphoma in both subcutaneous tumors and the ascites form implanted in mice. However, it resulted in the cure of only EAT-bearing mice. Results indicated that treatment-induced tumor control is primarily due to apoptosis rather than mitotic death[29] The labeling of S-phase cells with BrdU revealed that repopulation of cells may be responsible for the increased tumor burden observed following the initial reduction in tumor growth. Furthermore, partial response in the form of delayed tumor growth was also observed in nude mice-bearing human osteosarcoma treated with a combination of 2-DG and adriamycin or non-small-cell lung carcinoma xenografts treated with paclitaxel and 2-DG. [30]

Although, these in vivo studies have shown that 2-DG can significantly modify the radiation and chemotherapeutic drug response under appropriate treatment conditions, the underlying mechanisms, besides modifications of cellular responses need to be clearly established. Cellular heterogeneity and therefore, the functional behavior of tumors, variable tumor physiology as well as host-tumor interactions are some of the factors that determine the tumor response to the combined treatment (radiation/drugs + 2-DG). Recent studies with multicellular tumor spheroids have clearly underlined the role of synergy between endogenous oxidative stress related to tumor (like TNF-α) and induced metabolic oxidative stress that leads to radio- and chemosensitization significantly higher than in monolayer cultures. [34],[35] The modulation of immune system has been shown to play an important role in the responses of tumors to many anticancer therapies. [36],[37],[38]


 > Immunomodulatory Effects of 2-DG Top


Glycolysis is critically involved in the activation and functional regulation of lymphocyte and other cells of the immune system. [39],[40] Therefore, it is suggested that immunomodulation may also contribute to the radio- and chemosensitization of tumors by the glycolytic inhibitor 2-DG, besides the direct effect on tumor cells. The modulation of some circulating proinflammatory cytokines and the restoration of CD4 + and CD8 + cells (in spleen) has been observed in responders during radiosensitization and chemosensitization by 2-DG. [29]

One of the key regulators of the immune system, T-regulatory cells (a subpopulation of CD4 + cells, T regs) maintain the peripheral homeostasis by inactivating self-reactive cells [41],[42] that is exploited by the cancer cells to suppress the immune system (antitumor immunity). Besides this, the T H 1 and T H 2 balance plays an important role in various diseases, [43] e.g., cancer. Enhanced T H 2 cytokines and T-regs with decreased T H 1 cytokines were found proportional to the growth of Ehrlich ascites tumors in mice, suggesting immune suppression. However, the combination (2-DG + radiation) decreased the T H 2 cytokines and T-regs and enhanced the T H 1 cytokines in responders (showing complete tumor regression) as compared to nonresponders. [44] These results suggest that immunomodulation in the form of restoration of the CD4 + and CD8 + ratio, a decrease in T-regs, and a shift from T H 2 to T H 1 showing strengthening of immune functions collectively contributes to the radiosensitization by 2-DG. Furthermore, our results also suggest that 2-DG does not compromise the survival of macrophages, but may induce alterations in the structure (increase in spreading) and function (increase in MHC class II expression, CD80 and CD86) that may stimulate the immune system contributing to the enhanced tumor regression observed earlier. [45]


 > Potentiating Radiosensitizing Effects of 2-DG Top


Heterogeneity in the radiosensitization among human tumor cell lines by 2-DG [10] and limited local tumor control observed in some of the animal tumors have prompted the development of approaches to enhance the radiosensitizing effects of 2-DG. In one such approach, 2-DG has been combined with 6-aminonicotinamide (6-AN) that inhibits HMP shunt pathway thereby enhancing the oxidative stress. in vitro and in vivo studies have indeed shown that the combination significantly enhances the degree of sensitization, that arises from the inhibition of repair processes coupled with the elevation of oxidative stress leading to enhanced cell death and local tumor control [20],[22] Since 2-DG as well as 6-AN causes disturbance in the functioning of the central nervous system, future studies critically examining the safety profile of the combination, vis-à-vis the doses of both the modifiers required for achieving therapeutic gain, should facilitate the design of appropriate treatment protocol. Alternatively, enhancing tumor glucose usage by tumor localizing agents such as hematoporphyrin derivatives [46] with intratumoral administration is one of the other novel approaches that needs to be investigated using animal models before contemplating application in clinics.


 > Normal Tissue Toxicity Top


Therapeutic gain is determined by the effects on both tumor proliferations leading to local tumor control and toxicity to the normal tissues. Therefore, the effects of 2-DG on radiation- and chemotherapeutic drug-induced damage in normal cells and tissues as well as systemic disturbances have also been investigated. Generally, a sparing effect or reduction in the damage to normal cells/tissues has been observed under conditions where 2-DG treatment leads to sensitization of tumor cells and tissues to radiation and chemotherapeutic drugs. [24],[29] The precise molecular mechanisms underlying the differential effects induced by 2-DG in tumors and normal tissues remain, however, yet to be completely understood. Nevertheless, the ability of 2-DG to differentially radiosensitize tumors and at the same time protect normal tissues against radiotoxicity makes it a strong candidate as an adjuvant for improving therapy of radioresistant tumors.


 > Conclusions Top


It is now apparent that cancer therapy needs to be individualized as the responses of patients to therapies are quite variable due to diverse biological behavior of tumors. in vitro studies from many human tumor cell lines have suggested that the degree of radio- and chemosensitization by 2-DG correlates well with the endogenous glucose usage among other parameters of energy metabolism, [10] with data on tumors in vivo supporting this proposition. [47] Further in vivo studies with different tumors and chemotherapeutic drugs are required for strengthening these observations. Since the glucose usage can be measured noninvasively using FDG-PET, it is expected to facilitate the individualization of the therapies using 2-DG (or other inhibitors) as an adjuvant in the radio- and chemotherapy of tumors. Since normal tissue tolerance is one of the limiting factors for the success of therapies, attempts should be made to enhance further the tolerance to higher doses of 2-DG, particularly reducing toxicity to the brain. Loco-regional administration, dietary modifications, or use of sedatives such as diazepam that reduce glucose utilization in the brain could serve to enhance tolerance to 2-DG. Low doses of 2-DG with the high-fat/low-carbohydrate ketogenic diet, [48] combination of 2-DG with inhibitors of the pentose phosphate pathway such as 6-aminonicotinamide, [22] and enhancing tumor glucose usage by tumor localizing agents such as hematoporphyrin derivatives [46] with intratumoral administration are some of the approaches that can be investigated in appropriate animal models, before contemplating clinical application.


 > Acknowledgements Top


We thank Professor Viney Jain for his guidance and constant encouragement during the course of many studies referred to in this review.

 
 > References Top

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