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

In order to improve the treatment of advanced H&N cancer we must consider to adopt new strategies as: new/better cytostatic agents; new combinations of present cytostatic agents and; potentiation of radiotherapy and cytostatic agents by biochemical modulation, which we define as potentiation of therapy by non-chemotherapeutic agents. The list of agents that can potentiate chemotherapy or circumvene resistance is comprehensive. Most of the data are derived from in vitro studies. Much attention has been given to the fact that calcium channel blocker (CCB) agents can circumvene the multi-drug resistance (MDR) phenotype. Cisplatin, 5-fluorouracil, bleomycin and methotrexate, toed in the treatment of head and neck cancer, are not part of the MDR phenotype. Still there 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 independent 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 nausea and vomiting. It has structural resemblance to some of the known inhibitors of the DNA associated enzyme poly ADPRT such as benzamide. Benzamide is however rather toxic. MCA has been shown to enhance the effect of CDDP in vivo as well as in permeabilized cells in vitro, indicating that the DNA damaging effect of MCA is not dependent on cytoplasmatic enzymes or messenger systems. Radiobiologists have pointed out important biologic characteristics about tumour tissue such as hypoxia in relation to tumour radiosensitivity. Nicotinamide can effect tumour radiosensitivity in vivo. Comparing the response of mice in skin and tumour under different gas breathing regimens a considerable therapeutic gain has been demonstrated for oxygen and carbon dioxide (95% O2 + 5% CO2) breathing mice. The effect of ionizing radiation (RT) on xenografted squamous cell carcinoma can also be enhanced by MCA. The optimal treatment interval is MCA given one hour before RT, which is in concordance with the hypothesis that MCA has to be present at the site of injury 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 irradiation, which indicates a potential therapeutic gain using MCA in a clinical setting. The above discussed interactions between biochemical modulators and chemo-/radio-therapeutic agents serve to illustrate the fruitfull 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 toxicity of normal tissue reaction.