pH and cancer: bicarb with/without chemo

[Rich66]

(ph regulator, clinical monotherapy benefit, w/Doxo?, w/Mitoxantrone, for cancer detection, proton pump inhib for pH?)

Cancer Research 69, 2260, March 15, 2009. Published Online First March 10, 2009;
doi: 10.1158/0008-5472.CAN-07-5575
© 2009 American Association for Cancer Research

Cell, Tumor, and Stem Cell Biology

Bicarbonate Increases Tumor pH and Inhibits Spontaneous Metastases

Ian F. Robey¹, Brenda K. Baggett¹, Nathaniel D. Kirkpatrick¹, Denise J. Roe¹, Julie Dosescu², Bonnie F. Sloane², Arig Ibrahim Hashim³, David L. Morse³, Natarajan Raghunand¹, Robert A. Gatenby³ and Robert J. Gillies^{3 1} Arizona Cancer Center, University of Arizona, Tucson, Arizona; ² Department of Pharmacology, Wayne State University, Detroit, Michigan; and ³ H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
Requests for reprints: Robert J. Gillies, H. Lee Moffitt Cancer Center, SRB-2, 12302 Magnolia Drive, Tampa, FL 33612. Phone: 813-725-8355; Fax: 813-979-7265; E-mail: Robert.Gillies@moffitt.org.

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Key Words: Acid-base • metastasis • breast tumor • xenografts • pH • sodium bicarbonate

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 NaHCO₃ 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 ³¹P magnetic resonance spectroscopy and the export of acid from growing tumors by fluorescence microscopy of tumors grown in window chambers. NaHCO₃ 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, NaHCO₃ 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. [Cancer Res 2009;69(6):2260–8]

Cancer Research 69, 2677, March 15, 2009. Published Online First March 10, 2009;
doi: 10.1158/0008-5472.CAN-08-2394
© 2009 American Association for Cancer Research

Tumor Microenvironment

The Potential Role of Systemic Buffers in Reducing Intratumoral Extracellular pH and Acid-Mediated Invasion

Ariosto S. Silva¹, Jose A. Yunes¹, Robert J. Gillies² and Robert A. Gatenby^{2 1} Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, Sao Paulo, Brazil and ² Departments of Radiology and Integrative Mathematical Oncology, Moffitt Cancer Center, Tampa, Florida
Requests for reprints: Robert A. Gatenby, Department of Radiology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612. Phone: 813-745-2843; Fax: 813-745-6070; E-mail: Robert.Gatenby@moffitt.org.

Key Words: tumor acidosis • mathematical model • sodium bicarbonate • computer simulations • tumor invasion

A number of studies have shown that the extracellular pH (pHe) in cancers is typically lower than that in normal tissue and that an acidic pHe promotes invasive tumor growth in primary and metastatic cancers. Here, we investigate the hypothesis that increased systemic concentrations of pH buffers reduce intratumoral and peritumoral acidosis and, as a result, inhibit malignant growth. Computer simulations are used to quantify the ability of systemic pH buffers to increase the acidic pHe of tumors in vivo and investigate the chemical specifications of an optimal buffer for such purpose. We show that increased serum concentrations of the sodium bicarbonate (NaHCO₃) can be achieved by ingesting amounts that have been used in published clinical trials. Furthermore, we find that consequent reduction of tumor acid concentrations significantly reduces tumor growth and invasion without altering the pH of blood or normal tissues. The simulations also show that the critical parameter governing buffer effectiveness is its pK_a. This indicates that NaHCO₃, with a pK_a of 6.1, is not an ideal intratumoral buffer and that greater intratumoral pHe changes could be obtained using a buffer with a pK_a of 7. The simulations support the hypothesis that systemic pH buffers can be used to increase the tumor pHe and inhibit tumor invasion. [Cancer Res 2009;69(6):2677–84]

1: Biochem Pharmacol. 2003 Oct 1;66(7):1207-18. Links

Tumor acidity, ion trapping and chemotherapeutics. I. Acid pH affects the distribution of chemotherapeutic agents in vitro.

Mahoney BP, Raghunand N, Baggett B, Gillies RJ.
Department of Biochemistry and Cancer Biology Program, Arizona Cancer Center, University of Arizona Health Sciences Center, Tucson, AZ 85724-5024, USA.
Resistance to anti-cancer chemotherapies often leads to regional failure, and can be caused by biochemical and/or physiological mechanisms. Biochemical mechanisms include the overexpression of resistance-conferring proteins. In contrast, physiological resistance involves the tumor microenvironment, and can be caused by poor perfusion, hypoxia and/or acidity. This communication investigates the role of tumor acidity in resistance to a panel of chemotherapeutic agents commonly used against breast cancer, such as anthracyclines, taxanes, anti-metabolites and alkylating agents. The effects of pH on the cytotoxicity of these agents were determined, and ion trapping was confirmed by monitoring the effect of pH on the cellular uptake of radiolabeled anthracyclines. Furthermore, pH-dependent cytotoxicity and uptake were compared between parental drug sensitive MCF-7 cells and variants overexpressing p-glycoprotein (MDR-1) and Breast Cancer Resistance Protein. These data indicate that the magnitude of physiological resistance from pH-dependent ion trapping is comparable to biochemical resistance caused by overexpression of drug efflux pumps. Hence, microenvironment-based ion trapping is a significant barrier to anthracycline-based chemotherapy and can itself be a therapeutic target to enhance the efficacy of existing chemotherapies.

This version of apparently the same study suggests benefit with Mitoxantrone but no benefit with Doxo??


2003 Elsevier Inc.
Tumor acidity, ion trapping and chemotherapeutics: II. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agents


References and further reading may be available for this article. To view references and further reading you must purchase this article.


Natarajan Raghunand^{, , 1}, Brent P. Mahoney¹ and Robert J. Gillies

Department of Biochemistry and Cancer Biology Program, Arizona Cancer Center, University of Arizona Health Sciences Center, Tucson, AZ 85724-5024, USA



Received 24 January 2003;
accepted 13 June 2003. ;
Available online 19 September 2003.

Abstract

Ion-trapping theory predicts that alkalinization of tumor extracellular pH will enhance the anti-tumor activity of weak-base chemotherapeutics. We have previously demonstrated that chronic and acute treatment of tumor-bearing mice with sodium bicarbonate results in tumor-specific alkalinization of extracellular pH. Furthermore, bicarbonate pretreatment enhances the anti-tumor activity of doxorubicin and mitoxantrone in two different mouse tumor models. Previous work has indicated subtle, yet significant differences between the pH sensitivities of the biodistribution and anti-tumor efficacies of doxorubicin and mitoxantrone in vitro. The present study demonstrates that systemic alkalinization selectively enhances tumor uptake of radiolabeled mitoxantrone, but not doxorubicin. Results using these two drugs are quantitatively and qualitatively very different, and can be explained on the basis of differences in the octanol–water partition coefficients of their charged forms. These results suggest that inducing metabolic alkalosis in patients would have a positive effect on response to mitoxantrone therapy. However, the therapeutic index would not increase if sodium bicarbonate also caused increased retention of mitoxantrone in susceptible normal tissues in the host. The major dose-limiting organ systems for mitoxantrone are heart, liver, bone marrow, spleen and blood cells. Bicarbonate was found to have no significant effect on the distribution of mitoxantrone to any of these tissues except for spleen. However, neither spleen weights nor lymphocyte counts were adversely affected by NaHCO₃ pretreatment, indicating that this co-therapy does not enhance myelosuppression due to mitoxantrone therapy. These findings suggest that metabolic alkalosis would produce a net gain in mitoxantrone therapeutic index.

Author Keywords: Mitoxantrone; Doxorubicin; Alkalosis; Radio-label; Partition coefficient

Abbreviations: AUC, area-under-the-curve; FBS, fetal bovine serum; i.p., intraperitoneal; i.v., intravenous; pHe, extracellular pH; SCID, severe combined immunodeficient

Article Outline

1. Introduction

2. Materials and methods

2.1. Cells and tumor

2.2. Measurement of partition coefficients

2.3. Tumor growth statistics

2.4. Biodistribution of radiolabeled drugs

2.5. Chemotherapy

3. Results

3.1. NaHCO₃ enhances anti-tumor effects of anthracyclines but not taxol

3.2. Systemic alkalinization affects biodistribution and pharmacokinetics of mitoxantrone to a greater degree than doxorubicin

3.3. Mitoxantrone and doxorubicin exhibit different pH-dependent partition coefficients

3.4. Effect of alkalinization on mitoxantrone toxicity

4. Discussion

Acknowledgements

References

Fig. 1. Effect of NaHCO₃ on tumor growth. Animals bearing tumors were treated in four groups: saline, bicarbonate, drug, and drug+bicarbonate. Doses were as indicated, in mg/kg. M: mitoxantrone, T: taxol, D: doxorubicin. Tumor volumes were measured 3× per week and, from each individual growth curve, the time it took to reach 1.0 mL was scored. Bicarbonate alone had no significant effect on tumor growth rate (not shown).

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Fig. 2. Systemic alkalinization affects biodistribution and pharmacokinetics of mitoxantrone to a greater degree than doxorubicin. (A) Mitoxantrone concentration vs. time in C3H tumor tissue. Mitoxantrone content was assayed at 2, 6, and 18 hr and the values±SD are plotted (N=8) as a function of time following the administration of intravenous mitoxantrone. (B) Mitoxantrone concentration vs. time in the livers of C3H/Hen mice. Mitoxantrone content was assayed at 2, 6, and 18 hr and the values±SD are plotted (N=8) as a function of time following the administration of intravenous mitoxantrone. (C) Doxorubicin concentration vs. time in the MCF-7 human adenocarcinoma tumor tissue of SCID mice. Doxorubicin content was assayed at 2, 6, and 18 hr and the values±SD are plotted (N=8) as a function of time following the administration of intravenous doxorubicin. (D) Doxorubicin concentration vs. time in the liver of MCF-7 tumor bearing SCID mice. Doxorubicin content was assayed at 2, 6, and 18 hr and the values±SD are plotted (N=8) as a function of time following the administration of intravenous doxorubicin.
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Br J Cancer. 1999 Jun;80(7):1005-11.
Enhancement of chemotherapy by manipulation of tumour pH.

Raghunand N, He X, van Sluis R, Mahoney B, Baggett B, Taylor CW, Paine-Murrieta G, Roe D, Bhujwalla ZM, Gillies RJ.
Arizona Cancer Center, Tucson 85724-5024, USA.
The extracellular (interstitial) pH (pHe) of solid tumours is significantly more acidic compared to normal tissues. In-vitro, low pH reduces the uptake of weakly basic chemotherapeutic drugs and, hence, reduces their cytotoxicity. This phenomenon has been postulated to contribute to a 'physiological' resistance to weakly basic drugs in vivo. Doxorubicin is a weak base chemotherapeutic agent that is commonly used in combination chemotherapy to clinically treat breast cancers. This report demonstrates that MCF-7 human breast cancer cells in vitro are more susceptible to doxorubicin toxicity at pH 7.4, compared to pH 6.8. Furthermore 31P-magnetic resonance spectroscopy (MRS) has shown that the pHe of MCF-7 human breast cancer xenografts can be effectively and significantly raised with sodium bicarbonate in drinking water. The bicarbonate-induced extracellular alkalinization leads to significant improvements in the therapeutic effectiveness of doxorubicin against MCF-7 xenografts in vivo. Although physiological resistance to weakly basic chemotherapeutics is well-documented in vitro and in theory, these data represent the first in vivo demonstration of this important phenomenon.

PMID: 10362108 [PubMed - indexed for MEDLINE]



BBC news 2008

Bicarbonate 'could detect cancer'
The naturally-occurring chemical bicarbonate, used to make baking soda, could help detect cancer using sensitive scanning, research suggests.
Bicarbonate is involved in the body's balancing of acid and alkali.
But cancerous tissue is known to turn it into carbon dioxide.
The Cancer Research UK team found MRI scans were able to track changes in the chemical and therefore identify cancers even in the very early stages.

Almost all cancer has a lower pH, meaning it is more acidic than surrounding tissue.
Working with mice, the researchers boosted the MRI sensitivity more than 20,000 times, the Nature journal reported.
'Early warning system'
They said such precision could be used to detect tumours and to find out if cancer treatments are working effectively at an earlier stage.
Currently, there is no way to safely measure differences in pH in patients, but spotting these areas of acidity could be used to find cancers when they are very small.
Lead researcher Professor Kevin Brindle, from Cancer Research UK's Cambridge Research Institute at the University of Cambridge, said: "This technique could be used as a highly-sensitive early warning system for the signs of cancer.
"By exploiting the body's natural pH balancing system, we have found a potentially safe way of measuring pH to see what's going on inside patients.
Treatment response
"MRI can pick up on the abnormal pH levels found in cancer and it is possible that this could be used to pinpoint where the disease is present and when it is responding to treatment."
Using MRI, they looked to see how much of the tagged bicarbonate was converted into carbon dioxide within the tumour. In more acidic tumours, more bicarbonate is converted into carbon dioxide.
Fellow researcher Dr Ferdia Gallagher said: "Although it's early days, if this technique proves to be safe and effective in cancer patients it has the potential to be a crucial tool in detecting cancer earlier - which is often the key to successful treatment."
Dr Lesley Walker, director of cancer information at Cancer Research UK, said: "It's really important that we find new ways of diagnosing cancer earlier and find out if drugs are working well in the body.
"So if clinical trials show that this technique is as safe and effective in cancer patients as we expect, this could be a very useful tool in the early detection of cancer and may save many lives."


Story from BBC NEWS:
http://news.bbc.co.uk/go/pr/fr/-/2/h...th/7423304.stm

Published: 2008/05/28 16:57:26 GMT

© BBC MMIX




A related possible approach to the pH issue:

Expert Opin Pharmacother. 2005 Jun;6(7):1049-54.
Proton pump inhibitors may reduce tumour resistance.

De Milito A, Fais S.
Resistance to cytotoxic agents is a major problem in treating cancer. The mechanisms underlying this phenomenon appear to take advantage of functions involved in the control of cell homeostasis. A mechanism of resistance may be alteration of the tumour microenvironment via changes in the pH gradient between the extracellular environment and the cell cytoplasm. The extracellular pH of solid tumours is significantly more acidic than that of normal tissues, thus impairing the uptake of weakly basic chemotherapeutic drugs and reducing their effect on tumours. An option to revert multi-drug resistance is the use of agents that disrupt the pH gradient in tumours by inhibiting the function of pumps generating the pH gradient, such as vacuolar H(+)-ATPases (V-H(+)-ATPases). PPIs (including omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole) are protonable weak bases which selectively accumulate in acidic spaces. Recent findings from our group have shown that PPI pretreatment sensitised tumour cell lines to the effect of cisplatin, 5-fluoro-uracil and vinblastine V-H(+)-ATPases pump protons across the plasma membrane and across the membranes of various intracellular compartments. Some human tumour cells, particularly those selected for multi-drug resistance, exhibit enhanced V-H(+)-ATPase activity. A class of V-H(+)-ATPase inhibitors, called proton pump inhibitors (PPIs), have emerged as the drug class of choice for treating patients with peptic diseases. These drugs inhibit gastric acid secretion by targeting the gastric acid pump, but they also directly inhibit V-H(+)-ATPases.. PPI pretreatment was associated with the inhibition of V-H(+)-ATPase activity and an increase of both extracellular pH and the pH of lysosomal organelles, consistent with a cytoplasmic retention of the cytotoxic drugs and targeting to the nucleus in the case of doxorubicin. In vivo experiments showed that oral pretreatment with omeprazole induced a sensitivity of the human solid tumours to anticancer drugs.

PMID: 15957961 [PubMed - indexed for MEDLINE]


Int J Cancer. 2009 Oct 28. [Epub ahead of print]
pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity.

De Milito A, Canese R, Marino ML, Borghi M, Iero M, Villa A, Venturi G, Lozupone F, Iessi E, Logozzi M, Mina PD, Santinami M, Rodolfo M, Podo F, Rivoltini L, Fais S.
Department of Therapeutic Research and Medicines Evaluation, Unit of Antitumor Drugs, Istituto Superiore di SanitÃ*, Rome, Italy.
Metastatic melanoma is associated with poor prognosis and still limited therapeutic options. An innovative treatment approach for this disease is represented by targeting acidosis, a feature characterizing tumor microenvironment and playing an important role in cancer malignancy. Proton pump inhibitors (PPI), such as esomeprazole (ESOM) are prodrugs functionally activated by acidic environment, fostering pH neutralization by inhibiting proton extrusion. We used human melanoma cell lines and xeno-transplated SCID mice to provide preclinical evidence of ESOM antineoplastic activity. Human melanoma cell lines, characterized by different mutation and signaling profiles, were treated with ESOM in different pH conditions and evaluated for proliferation, viability and cell death. SCID mice engrafted with human melanoma were used to study ESOM administration effects on tumor growth and tumor pH by magnetic resonance spectroscopy (MRS). ESOM inhibited proliferation of melanoma cells in vitro and induced a cytotoxicity strongly boosted by low pH culture conditions. ESOM-induced tumor cell death occurred via rapid intracellular acidification and activation of several caspases. Inhibition of caspases activity by pan-caspase inhibitor z-vad-fmk completely abrogated the ESOM-induced cell death. ESOM administration (2.5 mg kg(-1)) to SCID mice engrafted with human melanoma reduced tumor growth, consistent with decrease of proliferating cells and clear reduction of pH gradients in tumor tissue. Moreover, systemic ESOM administration dramatically increased survival of human melanoma-bearing animals, in absence of any relevant toxicity. These data show preclinical evidence supporting the use of PPI as novel therapeutic strategy for melanoma, providing the proof of concept that PPI target human melanoma modifying tumor pH gradients.

PMID: 19876915 [PubMed - as supplied by publisher]