Year : 2009 | Volume
: 5 | Issue : 9 | Page : 21--26
Clinical studies for improving radiotherapy with 2-deoxy-D-glucose: Present status and future prospects
BS Dwarakanath1, Dinesh Singh2, Ajit K Banerji3, Rajiv Sarin4, NK Venkataramana5, R Jalali4, PN Vishwanath5, BK Mohanti6, RP Tripathi1, VK Kalia7, Viney Jain8,
1 Institute of Nuclear Medicine and Allied Sciences, Delhi, India
2 Dharmshila Cancer Hospital, New Delhi, India
3 Vidyasagar Institute of Mental Health and Neurosciences, New Delhi, India
4 Tata Memorial Hospital, Mumbai, India
5 NS Global, Bangalore, India
6 All India Institute of Medical Sciences, New Delhi, India
7 National Institute of Mental Health and Neurosciences, New Delhi, India
8 Eco-Development Foundation, New Delhi, India
B S Dwarakanath
Institute of Nuclear Medicine and Allied Sciences, New Delhi - 110 054
Higher rates of glucose usage generally correlate with poor prognosis in several types of malignant tumours. Experimental studies (both in vitro and in vivo) have shown that 2-deoxy-D-glucose (2-DG), a glucose analog and glycolytic inhibitor, enhances radiation-induced damage selectively in tumor cells while protecting normal cells, thereby suggesting that 2-DG can be used as a differential radiomodifier to improve the efficacy of radiotherapy. Clinical trials undertaken to study the feasibility, safety, and validity of this suggested approach will be described. Based on 2-DG-induced radiosensitization observed in primary organ cultures of cerebral glioma tissues, clinical trials were designed taking into consideration the radiobiology of gliomas and pharmacokinetics of 2-DG. Phase I/II clinical trials have unequivocally demonstrated that a combination of 2-DG (200-300 mg 2-DG per kg body weight orally administered after overnight fasting, 20min before irradiation) with large weekly fractions (5 Gy/fraction) of low-LET radiotherapy is well tolerated without any acute toxicity or late radiation damage to the normal brain tissue. Nonserious transient side effects similar to hypoglycemia induced disturbances like restlessness, nausea, and vomiting were observed at the 2-DG doses used. Data from these trials involving more than 100 patients have clearly indicated a moderate increase in the survival, with a significant improvement in the quality of life with clinicopathological evidence of protection of normal brain tissue. A phase III multicentric trial to evaluate the efficacy of the combined treatment is in progress. Directions for future studies are discussed.
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Dwarakanath B S, Singh D, Banerji AK, Sarin R, Venkataramana N K, Jalali R, Vishwanath P N, Mohanti B K, Tripathi R P, Kalia V K, Jain V. Clinical studies for improving radiotherapy with 2-deoxy-D-glucose: Present status and future prospects.J Can Res Ther 2009;5:21-26
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Dwarakanath B S, Singh D, Banerji AK, Sarin R, Venkataramana N K, Jalali R, Vishwanath P N, Mohanti B K, Tripathi R P, Kalia V K, Jain V. Clinical studies for improving radiotherapy with 2-deoxy-D-glucose: Present status and future prospects. J Can Res Ther [serial online] 2009 [cited 2019 Dec 8 ];5:21-26
Available from: http://www.cancerjournal.net/text.asp?2009/5/9/21/55136
Tumors utilize glucose at high rates to generate metabolic energy (ATP) and building blocks for macromolecular synthesis to sustain rapid cell proliferation. This manifests in an increased dependence on the glycolytic pathway (even in the presence of oxygen) for energy (ATP) supply as compared to surrounding normal tissues, a phenomenon first described almost 80 years ago by Warburg.  The glucose usage and aerobic glycolysis increase further during the tumor growth and advancement of malignancy due to the development of microregional hypoxia in most types of human tumors. While the enhanced glucose uptake is being increasingly exploited for the noninvasive detection and grading of tumors by positron emission tomography using the F-18-labeled glucose analog 2-deoxy-D-glucose (2-DG) (FDG-PET),  the development of therapeutic strategies based on this metabolic shift remains still a challenge.
The glucose analog 2-DG is the most widely investigated pharmacological agent in experimental and clinical oncology for targeting glucose metabolism. We describe briefly its scientific rationale, pharmacology, toxicity, and clinical studies, and future prospects of its use in cancer therapeutics.
Prominent Effects of 2-DG at the Molecular and Cellular Levels
2-DG competitively inhibits glucose transport (by sharing the same glucose transporters) and is phosphorylated by hexokinase (HK) to form 2-DG-6-phosphate, which is not metabolized further to any significant extent, and inhibits phosphohexoisomerase and glucose-6-phosphate dehydrogenase thereby reducing the output from glycolysis (ATP) and the pentose phosphate pathway (NAPDH). ,,,, 2-DG has also been found to alter N-linked glycosylation leading to unfolded protein responses and induce changes in gene expression and phosphorylation status of proteins involved in signaling, cell cycle control, DNA repair, calcium influx, and cell death via apoptosis.,, The inhibition of proliferation has been reported in many tumor cell lines, while studies on tumor-bearing animals have revealed a great deal of heterogeneity in growth inhibition. ,,,
Pharmacology and Toxicity of 2-DG in Human Subjects
Metabolic and clinical side effects induced by 2-DG have been investigated after intravenous, intra-arterial, and oral administration in normal human volunteers and in patients.
2-DG produces intracellular glucopenia since it competitively inhibits intracellular glucose utilization by inhibiting glucose transport, glycolysis, and pentose phosphate pathway. Most physiological effects induced by 2-DG result from decreases in the utilization of glucose by the central nervous system, some areas in the brain, particularly in the hypothalamus, being especially sensitive to intracellular glucopenia. To compensate for the intracellular glucopenia, a number of neurotransmitter systems are activated and several hormonal, metabolic, and behavioral responses are brought into play by the intact organism. Posterior and anterior pituitary hormone release, catecholamine-mediated glucocounter regulatory mechanisms, hunger and thirst are stimulated.  The stimulation of glucoreceptors in the hypothalamus leads to the activation of sympathetic neural pathways inducing increases in the secretions of epinephrine, growth hormone, and glucagon. Endogenous glucose is released from glycogen stores through catecholamine-mediated glycogenolysis, gluconeogenesis and lipolysis are stimulated by growth hormone leading to elevations of blood glucose, free fatty acids, lactate, and beta-hydroxybutyrate. ,,
Clinically, side effects similar to those of hypoglycemia, despite hyperglycemia in the blood, have been reported. The symptoms are transient lasting only for a couple of hours and can be reversed by the administration of glucose. No serious changes in vital parameters have been reported. The pulse rate may increase by about 15-20 beats per second up to 4h after 2-DG infusion, and then gradually comes to normal values. , No significant change in systolic blood pressure is observed; diastolic blood pressure has been reported to reduce by 10-30mmHg for about 90min in some studies.  Body temperature may fall initially (~1°C). Associated with the fall in the body temperature there is a feeling of warmth and sweating. The heat production increases gradually 2-3h after 2-DG administration. 2-DG has been shown to stimulate the gastric secretory vagus nerves and increase gastric secretion volume as well as pepsin output. ,
Treatment of Cancer Patients with 2-DG
In initial exploratory studies at the National Cancer Institute, Bethesda, USA, cancer patients (1 islet-cell carcinoma, 1 broncogenic carcinoma, 1 renal cell carcinoma, and 5 patients with leukemia) were given 2-DG intravenously during a 25-to 60-min period at doses ranging from 50 to 200 mg/kg body weight.  Blood glucose levels were observed to increase after 2-DG administration. Diaphoresis, generalized warmth, flushing, drowsiness, and hypothermia were noted. These side effects, similar to those of hypoglycemia, were not severe and most of them disappeared after about 90min of 2-DG infusion. An oral administration of 2-DG caused less side effects (equivalent to somewhat lower doses given intravenously). In some patients with leukemia, reduction in glycolysis and WBC counts was noted; however, there was no change in the course of the disease after a single infusion of 2-DG. It was realized that to achieve therapeutic effects, high doses of 2-DG would be required to be administered continuously for a long period of time. In view of the risk of toxicity of such a regimen, further trials to treat cancer with 2-DG were discontinued.
2-DG as a Differential Modifier of Repair Pathways to Optimize Tumor Radiotherapy
A more promising and feasible approach in cancer treatment was suggested by Jain and colleagues, based on their studies on the energy dependence of repair of radiation damage in wild-type and respiratory-deficient mutants of yeast cells. ,,, Since the cellular responses to radiation/chemical injury are known to be profoundly influenced by competitions between the processes of error-free repair, misrepair, and the fixation of potentially lethal damage, an appropriate modulation of the rates of these processes should provide an opportunity to optimize selective elimination of unwanted cells from the system. The error-free repair preferably occurs in resting cells while misrepair and fixation of lesions are facilitated by cell proliferation. Modulation in the rates of these processes can be achieved by altering the supply of metabolic energy.  Exploiting the facts that tumor cells show enhanced glucose utilization and derive a significant part of the metabolic energy through the glycolytic pathway, it was suggested that 2-DG could be used as a differential modifier of repair processes to reduce the repair of potentially lethal lesions in tumor cells while enhancing the same in normal tissues. , Such an application of 2-DG as an adjunct to enhance the efficacies of currently popular therapeutic agents such as radiation and/or cytotoxic drugs would not require continued presence of 2-DG for a long time. Subsequent in vitro and in vivo studies on various model systems have indeed shown selective enhancement of radiation-induced killing of malignant cells (sensitization) and a reduction in damage in normal cells (protection) by the presence of 2-DG for a short duration (couple of hours) after treatment with the therapeutic agents. 
While the exact molecular mechanisms underlying the 2-DG-induced differential modifications of damage responses are complex and remain yet to be elucidated in detail, appropriate combinations of tumoricidal agents such as ionizing radiations and chemotherapeutic drugs with 2-DG could provide unique opportunities to selectively destroy tumors, reduce toxicity to normal tissues, and significantly enhance the therapeutic efficacy. Therefore, we investigated the feasibility, safety, and therapeutic efficacy of 2-DG in combination with ionizing radiations in animal models and human cancer patients. The animal studies have been reviewed in an accompanying paper (Dwarakanath et al. in this issue); the studies with human cancer patients are reviewed in this paper.
131-I and 2-DG in Thyroid Carcinoma with Brain Metastasis : A Case Report
Thyroid cancer treatment with radioactive iodine provided a convenient first model to test the feasibility of the present approach, since functioning metastasis of thyroid cancer accumulates radioactive iodine and the response to therapy can be easily evaluated by gamma-ray scintillation scanning.
A preliminary study was conducted at All India Institute of Medical Sciences, New Delhi, on a patient (A.M., male, 54 years, 50 kg) suffering from follicular thyroid carcinoma with extensive metastasis in the neck, liver, and brain. Total thyroidectomy had been performed 3 years ago and three previous attempts of treatment with 131-I within a span of 2 years did not bring any significant benefit.
The patient was given 131-I (200mCi) on March 28, 1974, and two doses of 2-DG (10 g each in 150ml water, orally) after 16h and 65h of radioactive iodine administration. Glucose and 2-DG concentrations in the peripheral blood were measured at different intervals of time. In the peripheral blood of this patient, glucose levels started increasing after 1h, reaching peak values at 5h and returning to the base level by 24h after 2-DG administration; 2-DG/G molar concentration ratio around 1 or higher was achieved in the first 2 h. The patient showed typical symptoms of hypoglycemia 30min after 2-DG administration, which disappeared completely within 4h.
Gamma-ray scintigraphy on April 15, 1974, showed a marked reduction in the size of the primary and metastatic tumors. The patient was still alive in 1985 (14 years after initial diagnosis) with a remarkably improved quality of life. A whole-body scan revealed same number of metastatic lesions suggesting that the progress of disease could be arrested and the treatment of cancer with a combination of 2-DG with radiation might be feasible and safe warranting systematically planned clinical trials.
Systematic Phase I/II Clinical Trials on Malignant Cerebral Gliomas
Malignant gliomas are among the tumors most resistant to treatment; satisfactory therapy of malignant gliomas is not available at present and these tumors remain virtually incurable. The average survival time of patients with high-grade astrocytomas is less than 1 year with most patients dying within 3 years postdiagnosis. The human glioblastomas are known to regrow after postoperative radiotherapy and this local regrowth within the cranial cavity is largely responsible for killing the host. Therefore, an efficient reduction in the localized tumor mass and the inhibition of regrowth in this region may provide an effective cure. Gliomas are diffuse and heterogeneous tumors containing multiple regions of hypoxic and nonproliferating as well as euoxic and proliferating cell subpopulations. Hypoxic cells are known to be treatment resistant; however, glioblastoma cells, even under euoxic conditions, are intrinsically radio resistant due to efficient repair systems present in these cells. Therefore, based on 2-DG-induced radiosensitization observed in primary organ cultures of cerebral glioma tissues  and the clinical, metabolic, and radiobiologic aspects of this neoplasm, malignant gliomas were considered to be the most appropriate tumors for initial clinical studies to test the radiosensitization induced by 2-DG. Clinical trial protocols were designed taking into consideration the radiobiology of malignant cerebral gliomas, the pharmacology, and toxicity of 2-DG in humans and the timing of 2-DG administration with reference to tumor irradiation.
[Table 1] shows the phase I/II clinical trials completed so far. The protocol in phase I/II clinical trials consisted of four weekly fractions of 5 Gy per fraction administered 2-3 weeks postsurgery to the whole brain; 2-DG was given orally (200 mg/kg body weight) after overnight fasting and 20-30min before irradiation at 200 mg/kg body weight. Subsequently, a small field local radiation was delivered to the residual tumor plus a 3cm margin at a dose of 14Gy in seven equal fractions at five fractions/week. Results of these trials clearly established the safety and patient compliance to the combined treatment with a high radiation dose (5Gy) per fraction and 2-DG. The results indicated lack of any acute toxicity or late radiation damage  with a moderate increase in survival. Most importantly, the trial showed that the combination significantly enhances the quality of life.
Preclinical studies with human tumor cell lines and tumor-bearing animals have shown an increase in radiosensitization with increasing 2-DG doses. The normal tissue toxicity mainly in the form of CNS disturbances and cardiac toxicity could be limiting factors in using higher 2-DG doses, particularly in combination with a high radiation dose. Therefore, dose optimization studies were undertaken to examine the tolerance and safety of the escalating 2-DG dose during the combined treatment (2-DG + RT) in glioblastoma multiforme patients. The protocol in these trials was slightly modified from the previous phase I trial. Seven weekly fractions of the combined treatment 2-DG + radiation (5 Gy/fraction) were delivered to the postsurgery residual tumor plus 3cm margin as against four fractions to the whole brain [Table 1]. Results of this trial have shown excellent patient compliance and tolerance to the combined treatment up to a 2-DG dose of 250 mg/kg b.wt., without any acute or late toxicity. At a higher dose (300 mg/kg b.wt.), two out of six patients could not complete treatment due to restlessness in the first few (two to three) fractions, although the vital parameters were not altered  [Table 1]. Enhanced survival seen at 2-DG doses of 250-300 mg/kg b.wt. suggested that patients who can tolerate higher doses would in fact benefit the most from the combined treatment.
Based on the patient compliance observed during dose escalation studies, a single-arm multicentric phase II clinical trial has been carried out using a 2-DG dose of 250 mg/kg b.wt. with the same protocol that was employed in dose escalation studies. Results from more than 60 patients have clearly indicated an increase in the survival as compared to the conventional protocol [Table 1]. Interestingly, the enhancement in survival of patients with higher RPA scores (suggestive of poor prognosis) was significantly higher as compared to the values reported for treatment using temozolamide.  Again the quality of life of all patients during treatment and at extended follow-up times in surviving patients observed in this trial has reiterated the observations made in the earlier trials, suggesting that the combined protocol with hypofractionation and 2-DG does not result in late damage to the normal brain tissue. Indeed this trial also provided unequivocal clinicopathological evidences (in a few cases where re-exploration of the tumor was performed due to clinical conditions) of normal tissue protection concomitant with the destruction of the tumor. Well-preserved choroid plexus (normal brain tissue) adjoining extensive tumor necrosis was found in these patients (see the accompanying article in this issue by Venkataramana et al. ). Reasons for this well-preserved normal tissue could be related to the radiation fractionation regimen as well as biological factors. A total physical dose of 35 Gy used (7 ´ 5Gy/fraction) here is biologically equivalent (BED = 62Gy) to that given in the conventional treatment (60-65Gy) generally employed.  A reduction in the manifestations of radiation-induced damage and metabolic oxidative stress (leading to apoptosis and necrosis) and the restoration of normal cytokine profiles could be some of the biologic factors. Recent in vitro studies have indeed shown enhanced apoptosis in glioblastoma cells, but not in normal astrocytes, that could be linked to the maintenance of ATP levels and redox status in astrocytes. 2-DG-induced changes in the expression of certain genes related to apoptosis and alterations in the immune status including cytokine secretion in tumor-bearing mice have also been reported. , Further studies are required to understand the mechanisms underlying mechanisms of normal tissue protection, as it would allow the use of higher radiation doses for achieving better therapeutic efficacy.
A significant enhancement observed in the survival of two patients (out of three) who received the combined treatment at 300 mg/kg b.wt. of 2-DG (as compared to lower doses) and patient compliance without any life-threatening changes in vital parameters at this dose suggest that patients who can tolerate higher 2-DG doses may show greater benefit from the combined treatment. A pilot study was therefore initiated to evaluate the feasibility of administering the combined treatment at 5.5 Gy per fraction plus a 2-DG dose of 275 mg/kg b.wt. Preliminary observations in BMG patients treated with seven fractions of this combination have been quite encouraging with good patient compliance and lack of acute or late systemic or hematologic toxicity (Singh et al., to be published). It is pertinent to note that treatment protocols using hypofractionation with large radiation doses per fraction requires administration of 2-DG only once in a week, which is well tolerated and convenient for the patient. It is also cost effective and permits treatment of a larger number of patients per machine.
In line with the large radiation dose per fraction used in clinical trials with malignant brain tumors, , a clinical protocol for the treatment of glioblastoma with high-dose stereotactic radiosurgery was designed at the Kettering Medical Center, Kettering, Ohio, and approved by FDA, USA. Another clinical trial using similar protocol to treat intracranial metastatic lesions has been undertaken at the Iowa State University, USA. Results of this trial should provide a basis for the treatment of other inoperable neoplasms with radiosurgery and 2-DG.
Conclusions and Future Directions
The clinical trials on glioblastoma patients conducted so far suggest that the combination of hypofractionated radiotherapy with oral administration of 2-DG in doses between 250 and 300 mg/kg body weight is feasible and safe. Though the number of patients studied is small, clinical observations indicate improvements in the quality of life and a reduction in the late radiation damage to the normal brain tissue. The treatment protocol requires administration of 2-DG only once a week, is convenient for the patient, cost effective, and permits treatment of a larger number of patients per machine. Therefore, while dose escalation and phase III clinical trials on glioblastoma should be continued, studies incorporating treatment-resistant tumors at various other more common locations (lung, breast, and liver, for example) with similar protocols need to be undertaken.
Therapeutic nuclear medicine techniques using tumor-localizing radiopharmaceuticals offer attractive possibilities to treat metastatic disease; however, such applications have been limited so far because of the radiation-induced damage to bone-marrow cells resulting in hematological toxicities. The differential radioprotection induced by 2-DG in normal cells, particularly in the bone marrow and proliferating lymohocytes ,, is expected to reduce such toxicities. At the same time, sensitization of tumor cells to radionuclide-induced damage by 2-DG as reported in model systems , would enhance the therapeutic efficacy; the feasibility of using 2-DG in combination with radionuclide therapy has already been demonstrated in human patients of thyroid carcinoma. However, noteworthy in this context, is a preclinical study reporting reduction in the efficacy of radioimmunotherapy (RIT) by 2-DG,  which could be due to the limitations in designing an optimal treatment regimen with 2-DG and radionuclides.
The design of treatment regimens based on the knowledge of time-dependent changes in the metabolic and cell-signaling modifications caused by 2-DG vis-à-vis the time course of prosurvival and prodeath pathways is crucial for deriving optimal benefit from the combination. Since molecular and cellular processes related to survival and death of cells are initiated soon after irradiation and last for several minutes to few hours (and few days in the case of delayed metabolic oxidative stress), the design of protocols using 2-DG with internally administered radiopharmaceuticals is relatively more complex as compared to external beam radiotherapy. In the case of external beam RT, the temporal sequences of responses to 2-DG and radiation given at high dose rates can be better estimated, whereas in nuclear medicine therapeutic procedures, the induction of lesions is spread over a long time interval (depending on the half-life of radionuclides) overlapping the damage response events. Therefore, further systematic research work should be undertaken to optimize such regimens and to investigate the effects of combining 2-DG with radionuclide irradiation at continuously diminishing dose rates.
In view of the intertumor variability of therapeutic responses, future clinical studies should attempt to identify and select those patients most likely to benefit from the combined treatment of 2-DG plus radiation. Studies on monolayer cell cultures and spheroids (which mimic the microenvironment and variable physiology of tumors) of human tumor cell lines have suggested that the degree of radio- and chemosensitization induced by 2-DG correlates well with the endogenous glucose usage among other parameters of energy metabolism.  Recent data on animal tumors in vivo support this proposition.  Noninvasive and quantitative estimates of the glucose usage by FDG-PET, for example, could facilitate the individualization of the therapies using 2-DG as an adjuvant in the radio- and chemotherapy of tumors.
In future studies, attempts should be made to improve tolerance to higher doses of 2-DG, reduce induced toxicity, and further enhance the degree of tumor radiosensitization. A number of approaches are being investigated at the preclinical level. One such approach using a combination of 2-DG with 6-aminonicotinamide (6-AN), an inhibitor of the pentose phosphate pathway, has demonstrated that the combination significantly enhances the degree of sensitization even at lower doses of the inhibitors; , this appears promising and warrants clinical evaluation.
Clinical studies on cerebral gliomas were supported by DRDO, Government of India.
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