title: Acute metabolic alkalosis enhances response of C3H mouse mammary tumors to the weak base mitoxantrone.
abstract: 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.
authors.affiliation: University of Arizona Health Sciences Center, Cancer Center Division, 1515 North Campbell Avenue, Tucson, AZ 85724-5024, USA. raghunan@u.arizona.edu
authors.forename: N
authors.initials: N
authors.lastname: Raghunand
authors.forename: B
authors.initials: B
authors.lastname: Mahoney
authors.forename: R
authors.initials: R
authors.lastname: van Sluis
authors.forename: B
authors.initials: B
authors.lastname: Baggett
authors.forename: R J
authors.initials: RJ
authors.lastname: Gillies
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D017693:Sodium Bicarbonate; D008942:Mitoxantrone