Enhancement of chemotherapy by manipulation of tumour pH.
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.
Raghunand
N
N
Arizona Cancer Center, Tucson 85724-5024, USA.
He
X
X
van Sluis
R
R
Mahoney
B
B
Baggett
B
B
Taylor
C W
CW
Paine-Murrieta
G
G
Roe
D
D
Bhujwalla
Z M
ZM
Gillies
R J
RJ
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
D004317:Doxorubicin; D017693:Sodium Bicarbonate