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A phase I dose-escalation trial of 2-deoxy-d-glucose alone or combined with docetaxel in patients with advanced solid tumors

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Abstract

Purpose

This phase I trial was initiated to evaluate the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of the glycolytic inhibitor, 2-deoxy-d-glucose (2DG) in combination with docetaxel, in patients with advanced solid tumors.

Methods

A modified accelerated titration design was used. 2DG was administered orally once daily for 7 days every other week starting at a dose of 2 mg/kg and docetaxel was administered intravenously at 30 mg/m2 for 3 of every 4 weeks beginning on day 1 of week 2. Following the completion of dose escalation, cohorts of patients were then treated with 2DG for 21 days or every day of each 4-week cycle for up to 12 cycles.

Results

Thirty-four patients were enrolled: 21 on every other week, 6 on a 21 of 28-day cycle and 7 on the continuous 2DG dosing schedule. There were no dose-limiting toxicities which met the MTD criteria. The most common adverse events were fatigue, sweating, dizziness and nausea mimicking the hypoglycemic symptoms expected from 2DG administration. Therefore, 63 mg/kg was selected as the clinically tolerable dose. The most significant adverse effects noted at 63–88 mg/kg doses were reversible hyperglycemia (100 %), gastrointestinal bleeding (6 %) and reversible grade 3 QTc prolongation (22 %). Eleven patients (32 %) had stable disease, 1 patient (3 %) partial response and 22 patients (66 %) progressive disease as their best response. There was no PK interaction between 2DG and docetaxel.

Conclusion

The recommended dose of 2DG in combination with weekly docetaxel is 63 mg/kg/day with tolerable adverse effects.

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References

  1. Hu Y, Moraes C, Savaraj N, Priebe W, Lampidis TJ (2000) Rho(0) tumor cells: a model for studying whether mitochondria are targets for rhodamine 123, doxorubicin, and other drugs. Biochem Pharmacol 60(12):1897–1905

    Article  PubMed  CAS  Google Scholar 

  2. Liu H, Hu Y, Savaraj N, Priebe W, Lampidis T (2001) Hypersensitization of tumor cells to glycolytic inhibitors. Biochemistry 40(18):5542–5547

    Article  PubMed  CAS  Google Scholar 

  3. Maher J, Krishan A, Lampidis T (2004) Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-d-glucose in tumor cells treated under hypoxic vs aerobic conditions. Cancer Chemother Pharmacol 53(2):116–122

    Article  PubMed  CAS  Google Scholar 

  4. Boutrid H, Jockovich M, Murray T, Piña Y, Feuer W, Lampidis T, Cebulla CM (2008) Targeting hypoxia, a novel treatment for advanced retinoblastoma. Invest Ophthalmol Vis Sci 49(7):2799–2805

    Article  PubMed  Google Scholar 

  5. Maschek G, Savaraj N, Priebe W, Braunschweiger P, Hamilton K, Tidmarsh GF, De Young LR, Lampidis TJ (2004) 2-deoxy-d-glucose increases the efficacy of adriamycin and paclitaxel in human osteosarcoma and non-small cell lung cancers in vivo. Cancer Res 64(1):31–34

    Article  PubMed  CAS  Google Scholar 

  6. Warburg O (1956) On the origin of the cancer cells. Science 123(1391):309–314

    Article  PubMed  CAS  Google Scholar 

  7. Kim J-W, Dang C (2006) Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res 66(18):8927–8930

    Article  PubMed  CAS  Google Scholar 

  8. Shim H, Chun YS, Lewis BC, Dang CV (1998) A unique glucose-dependent apoptotic pathway induced by c-Myc. Proc Natl Acad Sci USA 95(4):1511–1516

    Article  PubMed  CAS  Google Scholar 

  9. Ramanathan A, Wang C, Schreiber S (2005) Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements. Proc Natl Acad Sci USA 102(17):5992–5997

    Article  PubMed  CAS  Google Scholar 

  10. Matoba S, Kang J, Patino W, Wragg A, Boehm M, Gavrilova O, Hurley P, Bunz F, Hwang P (2006) p53 regulates mitochondrial respiration. Science 16(312):1650–1653

    Article  Google Scholar 

  11. Landau BR, Laszlo J, Stengle J, Burk D (1958) Certain metabolic and pharmacologic effects in cancer patients given infusions of 2-deoxy-d-glucose. J Natl Cancer Inst 21(3):485–494

    PubMed  CAS  Google Scholar 

  12. Mohanti BK, Rath GK, Anantha N, Kannan V, Das BS, Chandramouli BA, Banerjee AK, Das S, Jena A, Ravichandran R, Sahi UP, Kumar R, Kapoor N, Kalia VK, Dwarakanath BS, Jain V (1996) Improving cancer radiotherapy with 2-deoxy-d-glucose: phase I/II clinical trials on human cerebral gliomas. Int J Radiat Oncol Biol Phys 35(1):103–111

    Article  PubMed  CAS  Google Scholar 

  13. Stein M, Lin H, Jeyamohan C, Dvorzhinski D, Gounder M, Bray K, Eddy S, Goodin S, White E, Dipaola RS (2010) Targeting tumor metabolism with 2-deoxyglucose in patients with castrate-resistant prostate cancer and advanced malignancies. Prostate 70(13):1388–1394

    Article  PubMed  CAS  Google Scholar 

  14. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216

    Article  PubMed  CAS  Google Scholar 

  15. Tsuchida Y, Therasse P (2001) Response evaluation criteria in solid tumors (RECIST): new guidelines. Med Pediatr Oncol 37(1):1–3. doi:10.1002/mpo.1154

    Article  PubMed  CAS  Google Scholar 

  16. Common Terminology Criteria for Adverse Events v3.0 (CTCAE) (2003). National Cancer Institute

  17. Teff KL, Elliott SS, Tschop M, Kieffer TJ, Rader D, Heiman M, Townsend RR, Keim NL, D’Alessio D, Havel PJ (2004) Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocrinol Metab 89(6):2963–2972

    Article  PubMed  CAS  Google Scholar 

  18. Duke W, Hirschowitz B, Sachs G (1965) Vagal stimulation of gastric secretion in man by 2-deoxy-d-glucose. Lancet 2(7418):871–876

    Article  PubMed  CAS  Google Scholar 

  19. Stalder GA, Schultheiss HR, Allgower M (1972) Use of 2-deoxy-d-glucose for testing completeness of vagotomy in man. Gastroenterology 63(4):552–556

    PubMed  CAS  Google Scholar 

  20. Burckhardt D, Stalder GA (1975) Cardiac changes during 2-deoxy-d-glucose test. A study in patients with selective vagotomy and pyloroplasty. Digestion 12(1):1–8

    Article  PubMed  CAS  Google Scholar 

  21. Gough AL, Keddie NC (1975) An assessment of the reproducibility and safety of 2-deoxy-d-glucose as a gastric acid stimulant in duodenal ulcer patients. Gut 16(3):171–176

    Article  PubMed  CAS  Google Scholar 

  22. Marfella R, Nappo F, De Angelis L, Siniscalchi M, Rossi F, Giugliano D (2000) The effect of acute hyperglycaemia on QTc duration in healthy man. Diabetologia 43(5):571–575

    Article  PubMed  CAS  Google Scholar 

  23. Zhang Y, Han H, Wang J, Wang H, Yang B, Wang Z (2003) Impairment of human ether-a-go–go-related gene (HERG) K + channel function by hypoglycemia and hyperglycemia. Similar phenotypes but different mechanisms. J Biol Chem 278(12):10417–10426

    Article  PubMed  CAS  Google Scholar 

  24. Hernlund E, Ihrlund LS, Khan O, Ates YO, Linder S, Panaretakis T, Shoshan MC (2008) Potentiation of chemotherapeutic drugs by energy metabolism inhibitors 2-deoxyglucose and etomoxir. Int J Cancer 123(2):476–483

    Article  PubMed  CAS  Google Scholar 

  25. Chatterjee S, Hirota H, Belfi CA, Berger SJ, Berger NA (1997) Hypersensitivity to DNA cross-linking agents associated with up-regulation of glucose-regulated stress protein GRP78. Cancer Res 57(22):5112–5116

    PubMed  CAS  Google Scholar 

  26. Yamada M, Tomida A, Yun J, Cai B, Yoshikawa H, Taketani Y, Tsuruo T (1999) Cellular sensitization to cisplatin and carboplatin with decreased removal of platinum-DNA adduct by glucose-regulated stress. Cancer Chemother Pharmacol 44(1):59–64

    Article  PubMed  CAS  Google Scholar 

  27. Mese H, Sasaki A, Nakayama S, Yokoyama S, Sawada S, Ishikawa T, Matsumura T (2001) Analysis of cellular sensitization with cisplatin-induced apoptosis by glucose-starved stress in cisplatin-sensitive and -resistant A431 cell line. Anticancer Res 21(2A):1029–1033

    PubMed  CAS  Google Scholar 

  28. Singh SP, Gao Y, Singh LD, Kunapuli SP, Ravindra R (1998) Role of microtubules in glucose uptake by C6 glioma cells. Pharmacol Toxicol 83(2):83–89

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank the patients who participated in this trial and the study coordinators, nurses, clinical research assistants and doctors who assisted with the research. This research is supported by Threshold Pharmaceuticals Inc.

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Authors do not have any disclosures.

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Correspondence to Theodore J. Lampidis.

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Raez, L.E., Papadopoulos, K., Ricart, A.D. et al. A phase I dose-escalation trial of 2-deoxy-d-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol 71, 523–530 (2013). https://doi.org/10.1007/s00280-012-2045-1

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  • DOI: https://doi.org/10.1007/s00280-012-2045-1

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