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.
Raghunand
N
N
University of Arizona Health Sciences Center, Cancer Center Division, 1515 North Campbell Avenue, Tucson, AZ 85724-5024, USA. raghunan@u.arizona.edu
Mahoney
B
B
van Sluis
R
R
Baggett
B
B
Gillies
R J
RJ
D000471:Alkalosis / Q000139:chemically induced / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008942:Mitoxantrone / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009368:Neoplasm Transplantation; D017693:Sodium Bicarbonate / Q000494:pharmacology / Q000627:therapeutic use; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D017693:Sodium Bicarbonate; D008942:Mitoxantrone