BIOCHEMICAL MODULATION OF CHEMOTHERAPY AND RADIOTHERAPY IN HEAD AND NECK-CANCER

In order to improve the treatment of advanced H&N cancer we must consi der to adopt new strategies as: new/better cytostatic agents; new comb inations of present cytostatic agents and; potentiation of radiotherap y and cytostatic agents by biochemical modulation, which we define as potentiation of therapy by non-chemotherapeutic agents. The list of ag ents that can potentiate chemotherapy or circumvene resistance is comp rehensive. Most of the data are derived from in vitro studies. Much at tention has been given to the fact that calcium channel blocker (CCB) agents can circumvene the multi-drug resistance (MDR) phenotype. Cispl atin, 5-fluorouracil, bleomycin and methotrexate, toed in the treatmen t of head and neck cancer, are not part of the MDR phenotype. Still th ere are a few interesting reports indicating that CCB's could enhanced the antitumour actions of cisplatin, and that this interaction may be : (a) very specific; (b) unique to each species of CCB and (c) is inde pendent of their binding affinity and classical function as inhibitors of the voltage sensitive calcium channels. Metoclopramide (MCA) is a structural analogue of procainamide used worldwide for preventing naus ea and vomiting. It has structural resemblance to some of the known in hibitors of the DNA associated enzyme poly ADPRT such as benzamide. Be nzamide is however rather toxic. MCA has been shown to enhance the eff ect of CDDP in vivo as well as in permeabilized cells in vitro, indica ting that the DNA damaging effect of MCA is not dependent on cytoplasm atic enzymes or messenger systems. Radiobiologists have pointed out im portant biologic characteristics about tumour tissue such as hypoxia i n relation to tumour radiosensitivity. Nicotinamide can effect tumour radiosensitivity in vivo. Comparing the response of mice in skin and t umour under different gas breathing regimens a considerable therapeuti c gain has been demonstrated for oxygen and carbon dioxide (95% O2 + 5 % CO2) breathing mice. The effect of ionizing radiation (RT) on xenogr afted squamous cell carcinoma can also be enhanced by MCA. The optimal treatment interval is MCA given one hour before RT, which is in conco rdance with the hypothesis that MCA has to be present at the site of i njury when RT is given in order to interact with repair mechanisms. We could not in conventional mice detect any MCP, induced enhancement of either acute skin reaction or in LD(50/30) after whole body irradiati on, which indicates a potential therapeutic gain using MCA in a clinic al setting. The above discussed interactions between biochemical modul ators and chemo-/radio-therapeutic agents serve to illustrate the frui tfull concept of biochemical potentiation of cytotoxicity. There is a promising potential for development of clinically useful applications with the use of drugs that enhance the tumour effect more than the tox icity of normal tissue reaction.