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Bicarbonate increases tumor pH and inhibits spontaneous metastases.

ABSTRACT: The external pH of solid tumors is acidic as a consequence of increased metabolism of glucose and poor perfusion. Acid pH has been shown to stimulate tumor cell invasion and metastasis in vitro and in cells before tail vein injection in vivo. The present study investigates whether inhibition of this tumor acidity will reduce the incidence of in vivo metastases. Here, we show that oral NaHCO(3) selectively increased the pH of tumors and reduced the formation of spontaneous metastases in mouse models of metastatic breast cancer. This treatment regimen was shown to significantly increase the extracellular pH, but not the intracellular pH, of tumors by (31)P magnetic resonance spectroscopy and the export of acid from growing tumors by fluorescence microscopy of tumors grown in window chambers. NaHCO(3) therapy also reduced the rate of lymph node involvement, yet did not affect the levels of circulating tumor cells, suggesting that reduced organ metastases were not due to increased intravasation. In contrast, NaHCO(3) therapy significantly reduced the formation of hepatic metastases following intrasplenic injection, suggesting that it did inhibit extravasation and colonization. In tail vein injections of alternative cancer models, bicarbonate had mixed results, inhibiting the formation of metastases from PC3M prostate cancer cells, but not those of B16 melanoma. Although the mechanism of this therapy is not known with certainty, low pH was shown to increase the release of active cathepsin B, an important matrix remodeling protease.

SUBMITTER: Robey IF

PROVIDER: S-EPMC2834485 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Bicarbonate increases tumor pH and inhibits spontaneous metastases.

Robey Ian F IF Baggett Brenda K BK Kirkpatrick Nathaniel D ND Roe Denise J DJ Dosescu Julie J Sloane Bonnie F BF Hashim Arig Ibrahim AI Morse David L DL Raghunand Natarajan N Gatenby Robert A RA Gillies Robert J RJ

Cancer research 20090310 6

The external pH of solid tumors is acidic as a consequence of increased metabolism of glucose and poor perfusion. Acid pH has been shown to stimulate tumor cell invasion and metastasis in vitro and in cells before tail vein injection in vivo. The present study investigates whether inhibition of this tumor acidity will reduce the incidence of in vivo metastases. Here, we show that oral NaHCO(3) selectively increased the pH of tumors and reduced the formation of spontaneous metastases in mouse mod ...[more]

PMID: 19276390

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Project description:BackgroundPatients with metastatic HER2/neu-positive (HER2/neu +) breast cancer (BC) often experience treatment resistance, disease recurrences and metastases. Thus, new approaches for improving the treatment of HER2/neu + BC to prevent metastatic dissemination are urgently needed. Our previous studies have shown that losartan, an angiotensin receptor blocker, increases tumor perfusion and decreases hypoxia in a number of tumor models. Hypoxia reduces the efficacy of radiation and increases metastases. We therefore hypothesized that by modifying tumor stroma and increasing oxygenation, losartan will improve the outcome of radiotherapy and inhibit disease progression in a highly metastatic HER2/neu + murine BC model.MethodsWe established a metastatic HER2/neu + murine BC line (MCa-M3C) and used it to generate mammary fat pad isografts in syngeneic female FVB/N mice. Starting on day 3 after orthotopic tumor implantation, we administered a 7-day losartan treatment (40 mg/kg BW, gavage daily); or a 7-day losartan treatment followed by 20 Gy single dose local irradiation (S-IR) on day 10 (tumor size ~ 100 mm3), or 20 Gy local fractionated (5 × 4 Gy daily) irradiation (F-IR) on days 10-14. We analyzed tumor-growth delay (TGD), development of spontaneous lung metastases, animal survival, tumor vascular density, and tumor hypoxia.ResultsTreatments with S-IR, F-IR, Losartan + S-IR, or Losartan + F-IR resulted in a significantly increased TGD (8-16 days) in MCa-M3C tumors versus controls. However, the combination of Losartan + S-IR and Losartan + F-IR further enhanced tumor response to radiation alone by increasing TGD an additional 5 to 8 days for both single and fractionated dose irradiation (P < 0.01), decreasing lung metastasis (Losartan + IR vs. Control, P < 0.025), and increasing animal survival (Losartan + IR vs. Control, P = 0.0303). In addition, losartan treatment significantly increased tumor vascularity (P = 0.0314) and decreased pimonidazole positive (hypoxic) area (P = 0.0002).ConclusionsCombining losartan with local irradiation significantly enhanced tumor response, at least in part via reduced tumor hypoxia presumably due to increased tumor perfusion. Our findings suggest that combining losartan with radiotherapy is a potential new treatment strategy for local control and inhibiting metastasis in HER2 + BC.

Project description:Rationale & Objective Excess morbidity and mortality are associated with both high and low serum bicarbonate levels in epidemiologic studies of patients with end-stage kidney disease (ESKD) receiving hemodialysis. The Kidney Disease Outcomes Quality Initiative (KDOQI) recommends modifying dialysate bicarbonate concentration to achieve a predialysis serum bicarbonate level ? 22 mmol/L, measured as total carbon dioxide (CO2). This practice assumes that total CO2 is an adequate surrogate for acid-base status, yet its surrogacy performance is unknown in ESKD. We determined acid-base status at the beginning and end of hemodialysis using total CO2 and pH and tested whether total CO2 is an appropriate surrogate for acid-base status. Study Design Pilot study. Setting & Participants 25 veterans with ESKD receiving outpatient hemodialysis. Tests Compared pH, calculated bicarbonate level, and total CO2. Outcomes The proportion of paired samples for which total CO2 misclassified acid-base status according to pH was determined. Bias of total CO2 was evaluated using Bland-Altman plots, comparing it to calculated bicarbonate. Results Among 71 samples, mean pH was 7.41 ± 0.03 predialysis and 7.48 ± 0.05 postdialysis. Compared with interpretation of full blood gas profiles, 9 of 25 (36%) participants were misclassified as acidemic using predialysis total CO2 measures alone (total CO2 < 22 mmol/L but pH ? 7.38); 1 (4%) participant was misclassified as alkalemic (total CO2 > 26 mmol/L but pH ? 7.42). Among paired samples in which predialysis total CO2 was < 22 mmol/L, the corresponding pH was acidemic (< 7.38) in just 3 of 13 (23%) instances. Limitations Small, single-center, entirely male cohort. Conclusions A majority of participants became alkalemic during routine hemodialysis despite arriving with normal pH. 10 of 25 (40%) participants’ acid-base status was misclassified using total CO2 measurements alone; the majority of predialysis total CO2 values that would trigger therapeutic modification according to practice guidelines did not have acidemia when assessed using pH. Efforts to improve dialysis prescription require recognition that total CO2 may not be reliable for interpreting acid-base status in hemodialysis patients. Graphical abstract

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Bicarbonate increases tumor pH and inhibits spontaneous metastases.

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Bicarbonate increases tumor pH and inhibits spontaneous metastases.

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