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2-Methoxyoestradiol-3,17-O,O-bis-sulphamate and 2-deoxy-D-glucose in combination: a potential treatment for breast and prostate cancer.

Tagg SL, Foster PA, Leese MP, Potter BV, Reed MJ, Purohit A, Newman SP - Br. J. Cancer (2008)

Bottom Line: In contrast, the inhibition of proliferation by 2DG was enhanced under hypoxia by 20 and 25% in MCF-7 and LNCaP cells, respectively.The combination of STX140 and 2DG in LNCaP cells under normoxia or hypoxia inhibited proliferation to a greater extent than either compound alone.This is the first study to show the benefit of combining a microtubule disruptor with 2DG in the two most common solid tumours.

View Article: PubMed Central - PubMed

Affiliation: Oncology Drug Discovery and Women's Health Group, Faculty of Medicine, Imperial College London, St Mary's Hospital, London W2 1NY, UK.

ABSTRACT
Drug combination therapy is a key strategy to improve treatment efficacy and survival of cancer patients. In this study the effects of combining 2-methoxyoestradiol-3,17-O,O-bis-sulphamate (STX140), a microtubule disruptor, with 2-deoxy-D-glucose (2DG) were assessed in MCF-7 (breast) and LNCaP (prostate) xenograft models in vivo. In mice bearing MCF-7 xenografts, daily p.o. administration of STX140 (5 mg kg(-1)) resulted in a 46% (P<0.05) reduction of tumour volume. However, the combination of STX140 (5 mg kg(-1) p.o.) and 2DG (2 g kg(-1) i.p.) reduced tumour volume by 76% (P<0.001). 2-Methoxyoestradiol-3,17-O,O-bis-sulphamate also reduced tumour vessel density. 2-Deoxy-D-glucose alone had no significant effect on tumour volume or vessel density. A similar benefit of the combination treatment was observed in the LNCaP prostate xenograft model. In vitro the degree of inhibition of cell proliferation by STX140 was unaffected by oxygen concentrations. In contrast, the inhibition of proliferation by 2DG was enhanced under hypoxia by 20 and 25% in MCF-7 and LNCaP cells, respectively. The combination of STX140 and 2DG in LNCaP cells under normoxia or hypoxia inhibited proliferation to a greater extent than either compound alone. These results suggest that the antiangiogenic and microtubule disruption activities of STX140 may make tumours more susceptible to inhibition of glycolysis by 2DG. This is the first study to show the benefit of combining a microtubule disruptor with 2DG in the two most common solid tumours.

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(A) Growth of MCF-7 tumours in athymic nude mice. Growth of MCF-7 tumours was inhibited by STX140 (5 mg kg−1 p.o.; daily) (*P<0.05) and STX140 (5 mg kg−1 p.o.; daily) + 2DG (2 g kg−1 i.p.; daily) (***P<0.001) after 28 days dosing relative to control. There was no effect on mouse weight throughout the study (inset), indicating a potential lack of compound toxicity. Points, mean percentage change in tumour volume; bars, s.e.m. (B) von Willebrand's factor staining of tumour sections. Administration of STX140 (5 mg kg−1 p.o.; daily) or STX140 (5 mg kg−1 p.o.; daily) + 2DG (2 g kg−1 i.p.; daily) caused a decrease in blood vessels relative to tumours taken from untreated animals. (C) H&E staining of tumour sections. No decrease in overall cell number was observed by H&E staining. Scale bar=100 μM, magnification × 200.
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fig5: (A) Growth of MCF-7 tumours in athymic nude mice. Growth of MCF-7 tumours was inhibited by STX140 (5 mg kg−1 p.o.; daily) (*P<0.05) and STX140 (5 mg kg−1 p.o.; daily) + 2DG (2 g kg−1 i.p.; daily) (***P<0.001) after 28 days dosing relative to control. There was no effect on mouse weight throughout the study (inset), indicating a potential lack of compound toxicity. Points, mean percentage change in tumour volume; bars, s.e.m. (B) von Willebrand's factor staining of tumour sections. Administration of STX140 (5 mg kg−1 p.o.; daily) or STX140 (5 mg kg−1 p.o.; daily) + 2DG (2 g kg−1 i.p.; daily) caused a decrease in blood vessels relative to tumours taken from untreated animals. (C) H&E staining of tumour sections. No decrease in overall cell number was observed by H&E staining. Scale bar=100 μM, magnification × 200.

Mentions: As no previous studies have investigated in vivo the combination of a microtubule disruptor and 2DG in breast and prostate cancer, the efficacy of STX140 and 2DG was assessed in the MCF-7 (ER-positive, breast) and LNCaP (AR-positive, prostate) xenograft models. In the breast cancer model (MCF-7) at the end of dosing (day 42), vehicle-treated tumours had increased in size by 1165±75% relative to the tumour starting volumes on day 14. Growth of MCF-7 tumours was significantly inhibited by STX140 (5 mg kg−1 p.o.; daily), tumours having increased in size by 664±135% (P<0.05). In mice treated with the combination of STX140 (5 mg kg−1 p.o.; daily) and 2DG (2 g kg−1 i.p.; daily) tumours increased in size only by 328±82% (P<0.001). The inset figure reveals that no weight loss occurred, indicating the potential absence of toxicity with these treatments (Figure 5A).


2-Methoxyoestradiol-3,17-O,O-bis-sulphamate and 2-deoxy-D-glucose in combination: a potential treatment for breast and prostate cancer.

Tagg SL, Foster PA, Leese MP, Potter BV, Reed MJ, Purohit A, Newman SP - Br. J. Cancer (2008)

(A) Growth of MCF-7 tumours in athymic nude mice. Growth of MCF-7 tumours was inhibited by STX140 (5 mg kg−1 p.o.; daily) (*P<0.05) and STX140 (5 mg kg−1 p.o.; daily) + 2DG (2 g kg−1 i.p.; daily) (***P<0.001) after 28 days dosing relative to control. There was no effect on mouse weight throughout the study (inset), indicating a potential lack of compound toxicity. Points, mean percentage change in tumour volume; bars, s.e.m. (B) von Willebrand's factor staining of tumour sections. Administration of STX140 (5 mg kg−1 p.o.; daily) or STX140 (5 mg kg−1 p.o.; daily) + 2DG (2 g kg−1 i.p.; daily) caused a decrease in blood vessels relative to tumours taken from untreated animals. (C) H&E staining of tumour sections. No decrease in overall cell number was observed by H&E staining. Scale bar=100 μM, magnification × 200.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2600694&req=5

fig5: (A) Growth of MCF-7 tumours in athymic nude mice. Growth of MCF-7 tumours was inhibited by STX140 (5 mg kg−1 p.o.; daily) (*P<0.05) and STX140 (5 mg kg−1 p.o.; daily) + 2DG (2 g kg−1 i.p.; daily) (***P<0.001) after 28 days dosing relative to control. There was no effect on mouse weight throughout the study (inset), indicating a potential lack of compound toxicity. Points, mean percentage change in tumour volume; bars, s.e.m. (B) von Willebrand's factor staining of tumour sections. Administration of STX140 (5 mg kg−1 p.o.; daily) or STX140 (5 mg kg−1 p.o.; daily) + 2DG (2 g kg−1 i.p.; daily) caused a decrease in blood vessels relative to tumours taken from untreated animals. (C) H&E staining of tumour sections. No decrease in overall cell number was observed by H&E staining. Scale bar=100 μM, magnification × 200.
Mentions: As no previous studies have investigated in vivo the combination of a microtubule disruptor and 2DG in breast and prostate cancer, the efficacy of STX140 and 2DG was assessed in the MCF-7 (ER-positive, breast) and LNCaP (AR-positive, prostate) xenograft models. In the breast cancer model (MCF-7) at the end of dosing (day 42), vehicle-treated tumours had increased in size by 1165±75% relative to the tumour starting volumes on day 14. Growth of MCF-7 tumours was significantly inhibited by STX140 (5 mg kg−1 p.o.; daily), tumours having increased in size by 664±135% (P<0.05). In mice treated with the combination of STX140 (5 mg kg−1 p.o.; daily) and 2DG (2 g kg−1 i.p.; daily) tumours increased in size only by 328±82% (P<0.001). The inset figure reveals that no weight loss occurred, indicating the potential absence of toxicity with these treatments (Figure 5A).

Bottom Line: In contrast, the inhibition of proliferation by 2DG was enhanced under hypoxia by 20 and 25% in MCF-7 and LNCaP cells, respectively.The combination of STX140 and 2DG in LNCaP cells under normoxia or hypoxia inhibited proliferation to a greater extent than either compound alone.This is the first study to show the benefit of combining a microtubule disruptor with 2DG in the two most common solid tumours.

View Article: PubMed Central - PubMed

Affiliation: Oncology Drug Discovery and Women's Health Group, Faculty of Medicine, Imperial College London, St Mary's Hospital, London W2 1NY, UK.

ABSTRACT
Drug combination therapy is a key strategy to improve treatment efficacy and survival of cancer patients. In this study the effects of combining 2-methoxyoestradiol-3,17-O,O-bis-sulphamate (STX140), a microtubule disruptor, with 2-deoxy-D-glucose (2DG) were assessed in MCF-7 (breast) and LNCaP (prostate) xenograft models in vivo. In mice bearing MCF-7 xenografts, daily p.o. administration of STX140 (5 mg kg(-1)) resulted in a 46% (P<0.05) reduction of tumour volume. However, the combination of STX140 (5 mg kg(-1) p.o.) and 2DG (2 g kg(-1) i.p.) reduced tumour volume by 76% (P<0.001). 2-Methoxyoestradiol-3,17-O,O-bis-sulphamate also reduced tumour vessel density. 2-Deoxy-D-glucose alone had no significant effect on tumour volume or vessel density. A similar benefit of the combination treatment was observed in the LNCaP prostate xenograft model. In vitro the degree of inhibition of cell proliferation by STX140 was unaffected by oxygen concentrations. In contrast, the inhibition of proliferation by 2DG was enhanced under hypoxia by 20 and 25% in MCF-7 and LNCaP cells, respectively. The combination of STX140 and 2DG in LNCaP cells under normoxia or hypoxia inhibited proliferation to a greater extent than either compound alone. These results suggest that the antiangiogenic and microtubule disruption activities of STX140 may make tumours more susceptible to inhibition of glycolysis by 2DG. This is the first study to show the benefit of combining a microtubule disruptor with 2DG in the two most common solid tumours.

Show MeSH
Related in: MedlinePlus