Acute metabolic alkalosis enhances response of C3H mouse mammary tumors to the weak base mitoxantrone.

Uptake of weak acid and weak base chemotherapeutic drugs by tumors is greatly influenced by the tumor extracellular/interstitial pH (pH(e)), the intracellular pH (pH(i)) maintained by the tumor cells, and by the ionization properties of the drug itself. The acid-outside plasmalemmal pH gradient in tumors acts to exclude weak base drugs like the anthracyclines, anthraquinones, and vinca alkaloids from the cells, leading to a substantial degree of "physiological drug resistance" in tumors. We have induced acute metabolic alkalosis in C3H tumor-bearing C3H/hen mice, by gavage and by intraperitoneal (i.p.) administration of NaHCO(3). (31)P magnetic resonance spectroscopic measurements of 3-aminopropylphosphonate show increases of up to 0.6 pH units in tumor pH(e), and 0.2 to 0.3 pH units in hind leg tissue pH(e), within 2 hours of i.p. administration of NaHCO(3). Theoretical calculations of mitoxantrone uptake into tumor and normal (hind leg) tissue at the measured pH(e) and pH(i) values indicate that a gain in therapeutic index of up to 3.3-fold is possible with NaHCO(3) pretreatment. Treatment of C3H tumor-bearing mice with 12 mg/kg mitoxantrone resulted in a tumor growth delay of 9 days, whereas combined NaHCO(3)--mitoxantrone therapy resulted in an enhancement of the TGD to 16 days.

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.

In vivo imaging of extracellular pH using 1H MRSI.

Tumor pH is physiologically important since it influences a number of processes relevant to tumorigenesis and therapy. Hence, knowledge of localized pH within tumors would contribute to understanding these processes. The destructiveness, poor spatial resolution, and poor signal-to-noise ratio (SNR) of current technologies (e.g., microelectrodes, 31P magnetic resonance spectroscopy) have limited such studies. An extrinsic chemical extracellular pH (pHe) probe is described that is used in combination with 1H magnetic resonance spectroscopic imaging to yield pHe maps with a spatial resolution of 1 x 1 x 4 mm3. The principle of the technique is demonstrated on a phantom. Further data are shown to demonstrate its application in vivo, and results agree with previously reported pH values. The accuracy of the reported pH measurements is <0.1 pH units, as derived from a detailed analysis of the errors associated with the technique, the description of which is included.

Plasmalemmal pH-gradients in drug-sensitive and drug-resistant MCF-7 human breast carcinoma xenografts measured by 31P magnetic resonance spectroscopy.

31p Magnetic resonance spectroscopy (MRS) was employed to investigate tumor pH in xenografts of drug-sensitive and drug-resistant MCF-7 human breast carcinoma cells. Measured extracellular pH values were found to be lower than the intracellular pH in all three tumor types investigated. The magnitude of this acid-outside plasmalemmal pH gradient increased with increasing tumor size in tumors of two drug-resistant variants of MCF-7 cells, but not in tumors of the parent (drug-sensitive) cells. The partitioning of weak-base or weak-acid drug molecules across the plasma membrane of a tumor cell is dependent upon the acid-dissociation constant (pKa) of the drug as well as the plasmalemmal pH gradient. A large acid-outside pH gradient, such as those seen in MCF-7 xenografts, can exert a protective effect on the cell from weak-base drugs such as anthracyclines and Vinca alkaloids, which have pKa values of 7.5 to 9.5. The possibility of enhancing the therapeutic efficacy of weak-base drugs by dietary or metabolic manipulation of the extracellular pH, in order to reduce or reverse the plasmalemmal pH gradient, deserves investigation.

Simultaneous localized 1H STEAM/31P ISIS spectroscopy in vivo.

A sequence for simultaneous acquisition of 1H STEAM and 31P ISIS spectra is described, and 1H and 31P spectra obtained simultaneously from the same volume of interest in both a phantom and a volunteer are presented. The STEAM and ISIS parts of the sequence use a common gradient scheme that is also used during the localized shimming process, partially compensating for eddy current effects. It is demonstrated that this method of simultaneous multinuclear spectroscopy does not compromise the localization performance of the sequence.

Increased NOE enhancement in 1H decoupled 31P MRS.

1H decoupling using the WALTZ-4 decoupling scheme is a popular means of improving spectral resolution in 31P NMR spectroscopy. At the same time, sensitivity in the proton decoupled 31P spectra is enhanced by the nuclear Overhauser effect. The authors show that when using WALTZ-4 decoupling in a uniform decoupler RF field, the degree of sensitivity enhancement is critically dependent on whether the decoupling interval contains an odd or an even number of WALTZ decoupling elements. This effect is demonstrated both in phantoms and in vivo.

Practical method for detecting poliovirus in anaerobic digester sludge.

A method has been developed which permits reliable detection of low numbers of poliovirus infective units in anaerobic digester sludge and dewatered composted sludge.