Ayesh, Riad; (1990) Studies on the pharmacogenetic aspects of bronchogenic carcinoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Bronchial carcinoma is not an inevitable consequence of smoking cigarettes. This thesis seeks to determine whether any one or more of the well established oxidative polymorphisms might directly control the biological response to cigarette smoking and/or environmental agents. 1. In the first part of the study, two groups (I and II) of European Caucasian patients were investigated with debrisoquine. Patients with lung cancer (n=245) and controls with airflow limitation (n=234) were similar in age (66.5 ± 7.4 (mean ± SD) and 67.2 ± 3.2 respectively), sex ratio ((M/F) 1.82, 1.89) and smoking history (60.3 ± 24.0 (mean ± SD), 59.4 + 21.1 pack year). Debrisoquine 4-hydroxylation showed major differences between lung cancer and control series. The metabolic ratios (MR) for smoking controls included 21 recessives and were distributed across the full range of values. On the other hand, the metabolic ratios for cancer patients contained only 4 recessives and were aggregated towards the left end of the spectrum of metabolic ratios. The relative risk for lung cancer for the extensive metabolisers of debrisoquine (MR<1) is 13 (95% CI : 4.0-43.3). Within this group, the risk for lung cancer increases further with possible and likely exposure to both asbestos and polycyclic aromatic hydrocarbons. The increased risk among this group with likely asbestos or polycyclic aromatic hydrocarbon exposure, is 35-fold and 17-fold respectively compared to non exposed poor and intermediate phenotypes. The debrisoquine hydroxylation status associated with lung cancer risk does not appear to be altered in any way by cigarette smoke or by the direct influence of the tumour mass. 2. A study was undertaken to eliminate the possibility of an enhanced, oxidative metabolism in lung cancer patients being an effect of the disease rather than associated with its cause. Two groups of patients (lung cancer (n=24) and controls (n=27) were investigated with both debrisoquine and mephenytoin. The % mephenytoin recovery as 4-hydroxymephenytoin was variable in both groups but statistically insignificant, 19 ± 11.8 mean + SD 21.6 ± 8.1 for cancer and controls respectively. The data showed no correlation between the debrisoquine metabolic ratios and the % mephenytoin recovery (rs=0.21 P>0.10). 3. A third study was undertaken to investigate the hepatic oxidation rates in lung cancer patients (n=30) and controls (n=29) as measured by antipyrine metabolism and to investigate the ability to metabolise both debrisoquine and antipyrine in both groups. The antipyrine clearance was almost identical in the two groups with mean ± SD 2.9 ± 0.46 L/h, 3.0 ± 0.5 in cases and controls respectively. The results also showed that there is no difference in the pharmacokinetic parameters of antipyrine between both extensive and poor metabolisers for debrisoquine hydroxylation. 4. The results of this thesis suggest a) that cigarette smokers who arc extensive metabolisers of debrisoquine are at an elevated risk of developing lung cancer, b) additive risk between the ability to extensively metabolise debrisoquine and occupational exposure to lung carcinogens in male smokers, c) the metabolic oxidation phenotypes may serve with other genetic markers for assessing susceptibility to lung cancer. 5. An agenda for subsequent investigations is proposed.

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