Enhancement of Delta Aminolevulinic Acid–Photodynamic Therapy In Vivo by Decreasing Tumor pH With Glucose and Amiloride

Abstract

Objectives/Hypothesis Delta aminolevulinic acid (ALA)–induced protoporphyrin IX (PpIX) is a fluorescent sensitizer that permits detection and treatment of squamous cell carcinoma of the oral cavity. An exogenously induced decrease in tissue pH was evaluated for its effect in enhancing cellular uptake of ALA and facilitating its transformation into PpIX. Study Design Mice grafted with HT29 colonic cancers had been given glucose and amiloride to modify the pH of tissues. Influence of pH changes has been evaluated on ALA‐induced PPIX fluorescence by optic fiber spectrofluorimetry as well as on tumor growth. Methods Results: The pH in HT 29 tumor decreased from 7.1 to 6.67 (P <.05) after intraperitoneal injection of glucose and amiloride. The PpIX fluorescence ratios in tumor or muscle before, between, and 2 hours after glucose and amiloride injection were not higher than control ratios. Aminolevulinic acid–photodynamic therapy was more efficient on HT 29 tumor–bearing mice when the pH value was decreased with glucose and amiloride, showing a difference in the tumor growth index ratio from the 1st to 14th day of 22% between amiloride‐glucose aminolevulinic acid–photodynamic therapy and aminolevulinic acid–photodynamic therapy alone (P <.05). Conclusions Glucose and amiloride did not change PpIX fluorescence in HT 29 tumor after intraperitoneal injection of aminolevulinic acid but enhanced aminolevulinic acid–photodynamic therapy efficacy. This was probably a result of mechanisms other than an increase in aminolevulinic acid cellular penetration and PpIX production, such as susceptibility to free radical toxicity or alteration of cellular repair enzymes under acidotic conditions. If a decrease of pH induces a more efficient photodynamic therapy as suggested by our results, an easier way to obtain this decrease than glucose and amiloride would be necessary for clinical applications.