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REVIEW ARTICLE
Year : 2009  |  Volume : 5  |  Issue : 9  |  Page : 32-35

Protection of normal cells and tissues during radio- and chemosensitization of tumors by 2-deoxy-D-glucose


1 Institute of Nuclear Medicine and Allied Sciences, New Delhi, India
2 Department of Biotechnology, Jamia Hamdard University, New Delhi, India

Date of Web Publication21-Aug-2009

Correspondence Address:
B S Dwarakanath
Institute of Nuclear Medicine and Allied Sciences, NewDelhi 110 - 054
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.55138

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 > Abstract 

Normal tissue toxicity is one of the major limiting factors in cancer therapy. Damage to normal tissues and critical organs restricts the use of higher therapeutic doses thereby compromising the efficacy. The glucose analog 2-deoxy-D-glucose (2-DG), an inhibitor of glycolytic ATP production has been shown to enhance radiation- and chemotherapeutic drug-induced damage in a number of cancer cells under in vitro and in vivo conditions while sparing or protecting normal cells. This review summarizes current understanding on the protection of normal cells and tissues against radiation- and chemotherapeutic drug-induced damage by 2-DG that makes this glucose analog an ideal adjuvant in cancer therapy.

Keywords: 2-Deoxy-D-glucose, ionizing radiation, chemotherapeutic drugs, peripheral blood lymphocytes, splenocytes, normal tissue toxicity


How to cite this article:
Farooque A, Afrin F, Adhikari J S, Dwarakanath B S. Protection of normal cells and tissues during radio- and chemosensitization of tumors by 2-deoxy-D-glucose. J Can Res Ther 2009;5, Suppl S1:32-5

How to cite this URL:
Farooque A, Afrin F, Adhikari J S, Dwarakanath B S. Protection of normal cells and tissues during radio- and chemosensitization of tumors by 2-deoxy-D-glucose. J Can Res Ther [serial online] 2009 [cited 2019 Sep 18];5:32-5. Available from: http://www.cancerjournal.net/text.asp?2009/5/9/32/55138


 > Introduction Top


Tolerance of the normal tissue is an important determinant of the success of various therapies currently used in the management of cancer. While acute side effects of radiotherapy with aggressive treatment protocols are dose limiting, affecting tumor control, late effects leading to organ failure and decreased quality of life are also a matter of concern, particularly in patients with enhanced survival. Damage to bone marrow cells and other critical organs such as heart, liver, kidney and brain generally contribute to the acute as well as late effects of radio- and chemotherapy.

Tumors require enhanced glucose usage to generate metabolic energy (ATP) and macromolecular synthesis for sustaining rapid cell proliferation. Increased dependency on glucose, the altered metabolic hallmark of cancer has been a target for developing cancer therapeutics. The glucose analog 2-deoxy-D-glucose (2-DG), an inhibitor of glycolytic ATP production, has been shown to enhance radiation- and chemotherapeutic drug-induced damage in a number of cancer cells under in vitro and in vivo conditions, by inhibiting repair and recovery processes as well as augmenting cell death selectively in cancer cells. [1],[2],[3],[4],[5],[6],[7],[8],[9] In normal cells, where energy is derived through the respiratory pathway, the energy supply is marginally affected by 2-DG that may not compromise the repair and recovery processes or even protect by reducing the rate of cell proliferation and fixation of primary molecular lesions, as the energy dependence of these processes appears to be different. [4] Several in vitro and in vivo studies have indeed confirmed that 2-DG spares the normal cells and tissues from radiation- and chemotherapeutic drug- induced damage under conditions that enhance tumor cell death and local tumor control. [10],[15],[17],[18] This review provides a brief account on the effects of 2-DG on normal cells and tissues both in vitro and in vivo during radio- and chemosensitization of tumors.


 > In Vitro Studies Top


Several studies have investigated the effects of 2-DG on normal cells in vitro that are pertinent either from the viewpoint of radio- and chemotherapy or cells from those organs that are more susceptible to the inhibition of glycolysis, like the normal brain. The hematopoietic system is most susceptible to damage caused by genotoxic agents like radiation and chemotherapeutic drugs. Early studies with human peripheral blood lymphocytes (hPBLs) from normal human volunteers irradiated under in vitro conditions clearly showed that the presence of 2-DG for a few hours after irradiation significantly reduced the radiation-induced cytogenetic damage. [10] Reduction in different types of chromosomal aberrations and micronuclei formation (indices of mitotic death) and DNA content dispersion have also been reported. Similar observations have been recently made in normal hPBL treated with chemotherapeutic drugs like bleomycin and mitomycin-C in vitro , with significant reductions in the frequency of drug-induced chromosomal aberrations and micronuclei formation. [11] Interestingly, both these studies reported an increase in the treatment-induced cytogenetic damage in established tumor cell lines and leukemic lymphocytes under these conditions, clearly indicating the differential modification of radiation damage in tumor and normal cells. Although a reduction in the proliferation-linked fixation of primary DNA lesions favored by a marginal decrease in the energy status has been suggested as one of the important mechanisms underlying this protection, it appears that many other factors contribute to this observed effect. Recent in vitro studies have shown that 2-DG is toxic to the glioblastoma cells but not the normal astrocytes under similar conditions of exposure, which appears to be linked to the maintenance of redox balance with no significant decrease in ATP levels of astrocytes. [12] It is also pertinent to mention that the repair of radiation-induced DNA damage studied by unscheduled DNA synthesis in organ cultures of the normal brain tissue obtained from the adjoining tumor area was not significantly altered in the presence of 2-DG.[13] While a reduction in the radiation-induced single-strand breaks (SSBs) analyzed using the comet assay has been reported in PBLs from cervical cancer patients incubated with 2-DG. [14]

Spleen and thymus are among the sensitive organs in the hematopoietic system with splenocytes and thymocytes susceptible to damage induced by radiation and a variety of chemotherapeutic drugs, compromising the immune system. Ex vivo studies with mouse splenocytes and thymocytes have shown that 2-DG reduces radiation-induced apoptosis at low radiation doses, while delaying the induction of apoptosis at higher doses. [15] In line with these observations, the presence of 2-DG for few hours did not significantly alter the CD4/CD8 ratios in splenocytes and thymocytes when irradiated in vitro , suggesting that it is not selectively toxic to a given subset of lymphocytes. [16]


 > In Vivo Studies Top


Damage to the bone marrow, one of the vital normal tissues, limits the use of higher therapeutic doses and therefore the efficacy of radiotherapy and chemotherapy. The intraperitoneal administration of 2-DG (1 g/kg body weight) just before whole-body irradiation of mice has not only been shown to reduce the frequency of chromosomal aberrations in bone marrow cells, but also enhance the animal survival. [17] Similar results have been reported in BrdU-sensitized tumor-bearing mice, where the administration of 2-DG significantly decreased the cytogenetic damage (micronuclei frequency) in bone marrow cells, without compromising the tumor sensitization. [18] Since bone marrow toxicity is a limiting factor in the radiosensitization of tumors, combining 2-DG with BrdU can be a useful approach to achieve differential toxicity and therefore enhanced therapeutic gain.

The immunological status not only determines the well-being of the animal, but also plays an important role in mounting the host defense response against the tumor. Moreover, glycolysis has been found to play an important role in the activation of lymphocytes, [19] which is mainly initiated from CD-28 co-stimulation. [20] Therefore, the modulation of glycolysis by the glycolytic inhibitor 2-DG, before the activation or after activation of lymphocytes by various antigenic stimuli, could have different effects on the final outcome like activation or suppression of the immune system. Single administration of 2-DG (i.v.) alone or in combination with focal irradiation of the normal mice (hind leg) has not been found to alter the hematopoietic and immune systems significantly as revealed by the status of several indicative parameters, namely, total leukocyte count (TLC), differential leukocyte count (DLC), CD4 + /CD8 + ratio, IL-2, IL-10, IFN-γmitogenic stimulation of splenocytes, etc. [16] However, frequently administered multiple doses (daily) may compromise the immune status in the form of reduced mitogenic stimulation in response to LPS and Con A and result in toxicity as well as altered host-tumor interactions. [21]

CD4 + cells play an important role in the immune system and are involved in several diseases like cancer and infectious diseases.[22],[23] 2-DG alone as well as in combination with radiation was found to decrease the T-regs population at different time points (especially induced, subpopulation of CD4 + ), while sparing the CD4 + cell population, which is required for the activated immune system. [24] Interestingly, 2-DG did not compromise the survival of peritoneal macrophages and macrophagic cell lines but increased the functionality of these cells. [25] It is pertinent to note that the combined treatment of 2-DG and etoposide (a topoisomerase II poison) resulted in an increase in the CD4 + /CD8 + ratio in Ehrlich ascites tumor-bearing mice, which correlated with the local tumor control and cure. [26]

Damage to critical organs like cardiac system and central nervous system may lead to life-threatening effects reflected in changes in vital parameters. Studies examining the effects of 2-DG on the cardiorespiratory system in mice and rats at doses used for radiosensitization (1-2 g/kg b.wt.) have shown transient changes in mean arterial blood pressure, heart rate, and respiratory rate, which did not result in any lethality. [27] The induction of hypothermia has also been observed. [28] Transient CNS disturbances in the form of slight drowsiness, loss of spontaneous eye movements, and a tendency to close the eyes have also been observed that generally last for 1-2 h followed by a complete recovery. [29] The systemic responses observed soon after the administration of pharmacological doses of 2-DG are similar to hypoglycemia, mainly due to glucocytopenia in the hypothalamus, causing alterations in the regulation of cardiorespiratory and immune systems, besides other normal tissues. [27] Since the in vivo half-life of 2-DG is 90-110min, the acute toxicity and symptoms are transitory followed by recovery without any intervention. However, a continuous administration of 2-DG for long duration (or daily administrations) could produce serious side effects, including immune disturbances [21] that may compromise cure rates despite enhanced local tumor control.


 > Clinical Studies Top


Early clinical studies employed 2-DG for assessing the completeness of vagotomy. No serious side effects were reported in these studies, although the 2-DG doses used were significantly lower than doses used (200- 300 mg/ kg b. wt.) during hypofractionated radiotherapy of malignant gliomas [30],[31] or in the treatment of other solid tumors. [32] Acute toxicity has not been reported in any of these trials that used different doses of 2-DG alone or as adjuvant to radiotherapy or chemotherapy. Mild-to-moderate nausea and vomiting were observed during the days of combined therapy in 50% patients without headache. However, no significant changes were noted in the vital parameters.[30],[31] No significant deterioration of the neurological status was observed during the treatment period. Interestingly, late radiation damage to the normal brain was also not observed as revealed by clinical and MR imaging studies even up to a 2-DG dose of 300 mg/kg b.wt., [30] suggesting that normal tissue is spared or protected against radiation damage by 2-DG. In line with these observations, recent studies have provided the first histopthalogical evidence of normal tissue protection, where well-preserved choroid plexus included in the treatment volume was seen in patients, who underwent re-exploration surgery following clinical disturbances. [33] This was accompanied by extensive tumor necrosis, thereby providing clinical evidences of differential responses between tumor and normal tissues during the combined treatment of 2-DG + hypofractionated radiotherapy of malignant brain tumors.

Although sparing of certain normal cells and tissues have been reported under in vitro and in vivo conditions, reduction in the toxicity to vital organs like brain and heart (cardiac toxicity) will enhance the success of therapies using 2-DG either as a therapeutic agent or as an adjuvant. Optimum design of protocols using novel approaches like the locoregional infusion of drugs and inhibitors is one of the strategies. The use of low doses of 2-DG combined with nontoxic doses of other metabolic inhibitors, yet producing sensitization could be an alternative strategy. Low doses of 2-DG with the high-fat/low-carbohydrate ketogenic diet [34] and the use of inhibitors of the pentose phosphate pathway such as 6-aminonicotinamide [35],[36] or selective inducers of glucose usage in tumors like hematoporphyrin derivatives [37] are some of the combinations that have been found to be effective in selectively enhancing tumor cell death and local tumor control. Dietary modifications or the use of sedatives such as diazepam that reduce glucose utilization in the brain could also be considered for enhancing tolerance to 2-DG.

Taken together, the current body of data available suggests that 2-DG by itself is not toxic to most of the normal cells under conditions that sensitize tumor cells to radiation and chemotherapeutic drugs. On the other hand, it protects the normal cells and tissues from treatment-induced damage in vitro and in vivo as well as in malignant glioma patients treated with a combination of 2-DG and hypofractionated radiotherapy.


 > Acknowledgements Top


We thank Professor Viney Jain for his guidance and constant encouragement during the course of many studies referred to in this review. This paper was presented at the Symposium on "Applications of 2-deoxy-D-glucose in the management of cancer," Institute of Nuclear Medicine and Allied Sciences, New Delhi, India, November 8-10, 2006.

 
 > References Top

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27.Vijayaraghavan R, Kumar D, Dube SN, Singh R, Pandey KS, Bag BC, et al . Acute toxicity and cardio-respiratory effects of 2-Deoxy- D-Glucose: A promising radiosensitizer. Biomed Environm Sci 2006;19:96-103.  Back to cited text no. 27
    
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