Impairment of drug metabolism in tumor-bearing animals

Summary.-A reduced response of a tumour to chemotherapy may be due to the host's drug metabolism. To test this hypothesis, we measured the metabolism of a model drug, para-aminosalicylate (PAS). Volunteers and cancer patients ingested a single oral dose (2 g) of PAS and we measured the plasma disappearance curve of the drug and its metabolite. In 7 patients suffering from lymphosarcoma, acute or chronic leukaemia and resistant to cancer chemotherapy, we observed low plasma PAS concentrations, an increase in PAS acetylation and an increased number (and a higher frequency) of abnormal liver-function tests. In 14 patients with malignant blood disease, yet responding well to chemotherapy, the metabolism of PAS is similar to that of healthy controls of the same age and sex. The plasma half-life of PAS is similar in sensitive and resistant patients, but slightly longer than in volunteers. Finally, in urine collected 120 min after drug administration, we observed the same results as in plasma. In conclusion, cancer patients resistant to chemotherapy do not metabolize the model drug PAS as volunteers or sensitive patients do, and this might be relevant to the terminal stage of the disease.

Section: Resultssupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

P-aminosalicylate metabolism in cancer patients sensitive and resistant to chemotherapy

Lavigne¹,

Barry²,

d'Auteuil³

et al. 1977

“…Those drugs known to affect metabolic ratio increase it, the bias thus operating against the result of fewer poor metabolisers among lung cancer cases. A biological effect of the cancer is a possible explanation, but in animal studies mono-oxygenase activities appear depressed by the presence of cancer (Rosso et al, 1971), such a bias again operating against the result . Steiner et al (1985) found that smoking and various other environmental factors such as alcohol, body weight and exercise that might differ between cases and controls did not demonstrably influence metabolic ratio, apart from a modest association with coffee intake.…”

mentioning

confidence: 99%

Debrisoquine metabolism and genetic predisposition to lung cancer

Law

Hetzel²,

Idel³

1989

It is usually the metabolites of environmental carcinogens that initiate a cancer (Miller & Miller, 1983), and if the metabolism were subject to genetically determined polymorphism, there could be variation between smokers in their susceptibility to smoking-related lung cancer. We report a case-control study using the drug debrisoquine as a potential marker of such genetically determined susceptibility to lung cancer.Debrisoquine has only one major metabolite, 4-hydroxy debrisoquine (Idle et al., 1979), and the extent of 4-hydroxylation before excretion is controlled by a single gene and segregates into two distinct phenotypes -autosomal recessive poor metabolisers (about 9% of white populations, hydroxylating only 1-2% of a 10mg dose of debrisoquine) and homozygous and heterozygous dominant extensive metabolisers (hydroxylating 10-99%) (Evans et al., 1980;Steiner et al., 1985). Unchanged and 4-hydroxy debrisoquine can be measured easily and with high reproducibility (r=0.88) in urine (Evans et al., 1980 We recruited consecutive caucasian inpatients with newly diagnosed lung cancer from a London hospital. Cigarette smoking histories were documented as accurately as possible and recorded in pack-years (one-twentieth the average daily number of cigarettes smoked multiplied by the number of years of smoking). Subjects whose total cigarette consumption was less than 10 pack years, or who had given up smoking more than five years previously were excluded. We also excluded patients with elevated serum bilirubin (>25mmoll-1), and those who were taking drugs known to induce oxidising enzymes (e.g. barbiturates) or to compete with debrisoquine for oxidation (Sloan et al., 1978;Eichelbaum, 1984). A total of 104 cases were included. The histological types were squamous cell (38 cases), large cell (22), small cell (31), adenocarcinoma (11) and undifferentiated (2), diagnosed histologically (92) or cytologically (12). The 104 control subjects were residents of three homes for ex-servicemen (70), inpatients with various non-malignant diseases (22) Cases and controls took a single 10mg debrisoquine tablet at 7 a.m. and made an 8 h urine collection, from which aliquots were stored at -20°C to await analysis by electroncapture gas-chromatography (Idle et al., 1979). The ratio of unchanged to 4-hydroxy debrisoquine concentration, the metabolic ratio, was used to assign phenotype, the antimode

“…* P < 0 05. centrate in the fat tissues, in lieu of its own metabolites. As demonstrated by several authors, the liver drug metabolizing enzyme activity is reduced in tumour bearing animals, leading to increased levels of unchanged drug and increased pharmacological effect or toxicity Kato, Takanaka and Oshima, 1968;Rosso, Dolfini and Donelli, 1968;Rosso et al, 1971;Bartosek et al, 1975;Fabro, 1971, 1975). Such a comparison between control and leukaemic mice is interesting because until now unusually high localization of cyclophosphamide in a specific organ has not been reported (Torkelson, LaBudde and Weikel, 1974 (Fig.…”

Section: Resultsmentioning

confidence: 95%

Increase in the gastrointestinal absorption and in tissue storage of cyclophosphamide in L-1210 leukaemic mice at an advanced stage of the disease

Lavigne¹,

Barry²,

d'Auteuil³

et al. 1975

Summary.-BDF' mice were inoculated with 106 leukaemic cells and, together with control mice, were given a single oral dose of cyclophosphamide-14C of 100 mg/kg body weight. In the leukaemic mice we observed an increased'4C concentration in the plasma, bone marrow, liver, lungs, spleen, kidney and particularly fat where the level was 2-4 times higher than in control mice. Conversely, during the same period, significantly less 14C was detected in the stomach and small intestine of the leukaemic mice. These results were obtained 6 days after tumour transplantation (median survival time 7*7 days) whereas no differences were observed when the studies were carried out 4 days after tumour transplantation. These findings indicate an increase in the gastrointestinal absorption and in the tissue storage of cyclophosphamide in L-1210 leukaemic mice at an advanced stage of the disease.