title: Enhancement of chemotherapy by manipulation of tumour pH.
abstract: 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.
authors.affiliation: Arizona Cancer Center, Tucson 85724-5024, USA.
authors.forename: N
authors.initials: N
authors.lastname: Raghunand
authors.forename: X
authors.initials: X
authors.lastname: He
authors.forename: R
authors.initials: R
authors.lastname: van Sluis
authors.forename: B
authors.initials: B
authors.lastname: Mahoney
authors.forename: B
authors.initials: B
authors.lastname: Baggett
authors.forename: C W
authors.initials: CW
authors.lastname: Taylor
authors.forename: G
authors.initials: G
authors.lastname: Paine-Murrieta
authors.forename: D
authors.initials: D
authors.lastname: Roe
authors.forename: Z M
authors.initials: ZM
authors.lastname: Bhujwalla
authors.forename: R J
authors.initials: RJ
authors.lastname: Gillies
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D017693:Sodium Bicarbonate / Q000494:pharmacology / Q000627:therapeutic use; D015996:Survival Rate; D014407:Tumor Cells, Cultured
chemical_list: D004317:Doxorubicin; D017693:Sodium Bicarbonate