Synergistic activity of troxacitabine (Troxatyl™) and gemcitabine in pancreatic cancer

Damaraju, Vijaya L.; Bouffard, David Y.; Wong, Clarence; Clarke, Marilyn L.; Mackey, John R.; Leblond, Lorraine; Cass, Carol E.; Grey, Mike; Gourdeau, Henriette

doi:10.1186/1471-2407-7-121

Cited by 27 publications

(21 citation statements)

References 21 publications

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“…Gemcitabine was administered as described (i.p. 80 mg/kg every 3 d) (31)(32)(33). In this trial, we detected a similar reduction in growth rate in the canagliflozin and gemcitabine arms.…”

Section: Is Sglt Functional Activity Correlated With Sglt Expression supporting

confidence: 65%

Functional expression of sodium-glucose transporters in cancer

Scafoglio

Hirayama

Kepe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

260

249

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Glucose is a major metabolic substrate required for cancer cell survival and growth. It is mainly imported into cells by facilitated glucose transporters (GLUTs). Here we demonstrate the importance of another glucose import system, the sodium-dependent glucose transporters (SGLTs), in pancreatic and prostate adenocarcinomas, and investigate their role in cancer cell survival. Three experimental approaches were used: (i) immunohistochemical mapping of SGLT1 and SGLT2 distribution in tumors; (ii) measurement of glucose uptake in fresh isolated tumors using an SGLT-specific radioactive glucose analog, α-methyl-, which is not transported by GLUTs; and (iii) measurement of in vivo SGLT activity in mouse models of pancreatic and prostate cancer using Me4FDG-PET imaging. We found that SGLT2 is functionally expressed in pancreatic and prostate adenocarcinomas, and provide evidence that SGLT2 inhibitors block glucose uptake and reduce tumor growth and survival in a xenograft model of pancreatic cancer. We suggest that Me4FDG-PET imaging may be used to diagnose and stage pancreatic and prostate cancers, and that SGLT2 inhibitors, currently in use for treating diabetes, may be useful for cancer therapy.SGLT2 | pancreatic cancer | prostate cancer | SGLT2-inhibitors P ancreatic cancer is the fourth-leading cause of cancer-related death in the United States (behind only lung, colon, and breast cancers), with 46,420 estimated new cases in 2014 and a mortality that almost equals incidence (39,590 estimated deaths in 2014); the overall 5-y survival rate is only 7% (seer.cancer.gov/statfacts/html/ pancreas.html). Prostate cancer is the most frequent cancer in men in the United States, with 233,000 estimated new cases in 2014. Despite widespread adoption of screening programs, prostate cancer is still the second-leading cause of cancer-related death in men, second only to lung cancer (seer.cancer.gov/statfacts/html/prost.

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“…Gemcitabine was administered as described (i.p. 80 mg/kg every 3 d) (31)(32)(33). In this trial, we detected a similar reduction in growth rate in the canagliflozin and gemcitabine arms.…”

Section: Is Sglt Functional Activity Correlated With Sglt Expression supporting

confidence: 65%

Functional expression of sodium-glucose transporters in cancer

Scafoglio

Hirayama

Kepe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

260

249

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“…However, in vivo, L-OddC had been reported to have a stronger antitumor activity than dFdC in several tumor models including Panc-1 (confirmed by us and data not shown; ref. 20), MiaPaCa model (dFdC refractory), and AsPC-1 (22). Here, we also showed L-OddC had a stronger inhibitory effect, than dFdC, on the growth of H460 tumor xenografts in a nude mouse model.…”

Section: Discussionmentioning

confidence: 49%

Effect of hypoxia on the expression of phosphoglycerate kinase and antitumor activity of troxacitabine and gemcitabine in non-small cell lung carcinoma

Lam

Bussom²,

Cheng³

2009

Molecular Cancer Therapeutics

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B-L-Dioxolane-cytidine (L-OddC; BCH-4556; troxacitabine), a novel L-configuration deoxycytidine analogue, was under clinical trials for treating cancer. The cytotoxicity of L-OddC is dependent on its phosphorylation to L-OddCTP by phosphoglycerate kinase (PGK) and its subsequent addition into nuclear DNA. Because PGK is induced with hypoxia, the expression of hypoxia-inducible factor-1A and PGK of H460 cells (human non-small cell lung carcinoma) in vitro and in vivo was studied. In culture, hypoxic treatment induced the protein expression of PGK by 3-fold but had no effect on the protein expression of other L-OddC metabolism-associated enzymes such as apurinic/apyrimidinic endonuclease-1, deoxycytidine kinase, CMP kinase, and nM23 H1. Using a clonogenic assay, hypoxic treatment of H460 cells rendered cells 4-fold more susceptible to L-OddC but not to gemcitabine (dFdC) following exposure to drugs for one generation. Using hypoxia response element-luciferase reporter system, Western blotting, and immunohistochemistry, it was found that hypoxiainducible factor-1A and PGK expression increased and could be correlated to tumor size. Despite dFdC being more toxic than L-OddC in cell culture, L-OddC (300 mg/kg i.p.) had a stronger antitumor activity than dFdC in H460 xenograft-bearing nude mice. Furthermore, L-OddC

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“…Standard therapeutic options for its treatment include surgery, radiation, and chemotherapy. Unfortunately, these therapies pose high risks [1,14]. Radiation induced necrosis, chemotherapy-associated side effects and secondary neoplasm are some of the most common long-term complications of chemotherapeutic treatment [2,3,18,58,59].…”

Section: Discussionmentioning

confidence: 99%

“…Pancreatic adenocarcinoma is a cancer notorious for its late presentation, early and aggressive local invasion with metastatic potential and poor outcome [1]. It is complicated to treat with an overall 5-year survival rate of <5% and a median overall survival of <6 months for the patients [2].…”

Section: Introductionmentioning

confidence: 99%