MODULATION OF RADIATION RESPONSE OF HUMAN TUMOR-CELLS BY THE DIFFERENTIATION INDUCERS, PHENYLACETATE AND PHENYLBUTYRATE

The aromatic fatty acids phenylacetate (PA) and phenylbutyrate (PB) ar e never antitumour agents currently under clinical evaluation. Their a bility to induce tumour differentiation in laboratory models and their low clinical toxicity profile makes them promising candidates for com bination with conventional therapies. In the present studies, we chara cterized the interactions between these aromatic fatty acids and radia tion, using as a model cell lines derived from cancers of the prostate , breast, brain and colon. Analysis of the radiation response of the t umour lines using the linear-quadratic model, demonstrated that cellul ar exposure to pharmacological, non-toxic concentrations of either PA or PB resulted in time-dependent and contrasting changes in radiation response. While drug pretreatment for 24 h reduced radiation sensitivi ty (significant alterations in both alpha and beta parameters), pre tr eatment for 72 h significantly increased radiosensitivity (significant alterations in alpha and beta parameters). In replicating tumour cell s, these changes were accompanied by a gradual G(I)-phase arrest. Cyto stasis alone, however, could not explain radiosensitization, as simila r alterations in radiation response were documented also in non-cyclin g cells. Modulation of tumour radiobiology by PA and PB was tightly co rrelated with early rise followed by decline in intracellular glutathi one levels and the activity of antioxidant enzymes such as catalase, s uperoxide dismutase, glutathione reductase, glutathione peroxidase and glutathione S-transferase. Although in vitro findings identify the ar omatic fatty acids PA and PB as a new class of non-toxic modulators of radiation response, the antagonistic effect of these compounds on rad iation response needs further examination. Our data strongly suggest t hat for PA or PB to have a role in clinical radiotherapy, appropriate scheduling of combination therapies must take into account their time- dependent effects in order to achieve clinical radiosensitization.