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 uptak e of weakly basic chemotherapeutic drugs and, hence, reduces their cytotoxi city. This phenomenon has been postulated to contribute to a 'physiological ' resistance to weakly basic drugs in vivo. Doxorubicin is a weak base chem otherapeutic agent that is commonly used in combination chemotherapy to cli nically treat breast cancers. This report demonstrates that MCF-7 human bre ast cancer cells in vitro are more susceptible to doxorubicin toxicity at p H 7.4, compared to pH 6.8. Furthermore P-31-magnetic resonance spectroscopy (MRS) has shown that the pHe of MCF-7 human breast cancer xenografts can b e effectively and significantly raised with sodium bicarbonate in drinking water. The bicarbonate-induced extracellular alkalinization leads to signif icant 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 re present the first in vivo demonstration of this important phenomenon.