Chemoradiotherapy - mechanism of increased cytostatics activation during the post-radiation reaction.


Klin Onkol 2005; 18(3): 92-97.

Abtract: Chemoradiotherapy employing nucleoside analogues, esp. fluorinated pyrimidines became a standard treatment approach in a variety of malignant tumours. Its mechanism of effect has not been discovered in detail. The introduction of capecitabine initiated a detailed investigation of the original concept of enhanced pyrimidine activation to active forms caused by an induction of pyrimidine metabolizing enzymes in a scope of a post-radiation reaction. A wide spectrum of cytokines and enzymes is induced by an irradiation including metabolic enzymes – thymidine phosphorylase (TP), thymidine kinase (TK), dihydropyrimidine dehydrogenase (DPD), thymidylate synthetase (TS), deoxycytidine kinase (dCK), deoxycytidine monophosphate kinase (dCMPK) and deoxycytidine deaminase (dCyD). These enzymes metabolize pyrimidine nucleoside analogues – 5-fluorouracil, capecitabine, ara-C and gemcitabine. Either an enhanced transcription of the relevant mRNA or an increased protein content or both had been found in irradiated cells. A ratio between the enhancement of anabolising and catabolising enzymes (TP/DPD) favours the increased anabolism of nucleoside analogues to active forms. The post-radiation reaction in a spectrum of proteins is long lasting. The increased protein content is apparent in a period between 24 hours and 5 days after the irradiation by a dose of 2 – 10 Gy. The increased transcription initiates within 24 hours, including early reactions within the first hour after the irradiation. Quantitatively there is a variability of post-radiation reactions related to the kind of the irradiated tissue. There is a more intensive induction of metabolic enzymes in tumour tissue than in a normal (non-tumour) tissue indicating a potential of cytostatic effect selectivity. The available references originate predominantly from tissue cultures or experimental animal tumour xenografts. So far only minimal practical measures can be derived from the information on mechanism of cytostatic effect potentiation. The current information supports the established regimens of a continuous administration of 5-FU and capecitabine. An individual assessment of a post-radiation reaction applicable for a prediction of a chemoradiation effect is not within the compass of our care.

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