Determination of drug effect on tumour cells, host animal toxicity and drug pharmacokinetics in a hollow-fibre model in rats

Purpose: Based on the previously published hollow-fibre assay mainly used f or early in vivo anticancer drug screening, we wanted to develop an extende d hollow-fibre model in which antitumour activity, haematological toxicity and pharmacokinetics could be studied in the same animal. Method: The breas t cancer cell lines MDA-MB-231 and MCF-7 were cultured in semipermeable hol low fibres. The fibres were implanted subcutaneously into immunocompetent m ale Sprague Dawley rats, and the rats: were treated with 5-fluorouracil (5- FU, 125 mg/kg), epirubicin (EPI. 10 mg/kg) or cyclophosphamide (CP, 120 mg/ kg) intraperitoneally, the new cyanoguanidine CHS 828 (375 mg/kg or 75 mg/ kg x 5) orally, or vehicle only. After 6 days the fibres were retrieved and the cell density was evaluated. Haematological parameters were monitored a nd two to four samples per animal were dl awn to determine the pharmacokine tic parameters in NONMEM. Results: Drug treatment had generally low effects on the tumour cells. Of the standard drugs (5-FU, EPI and CP), only CP exe rted a statistically significant antiproliferative effect.. CHS 828 had onl y a minor effect as a single dose, but divided into five daily doses had a pronounced effect on both cell lines. 5-FU, EPI and CP all caused a marked decrease in leucocytes, platelets and haemoglobin, while CHS 828 did not se em to affect these parameters. The pharmacokinetics of 5-FU and EPI were in accordance with previously established pharmacokinetic models. The pharmac okinetics of CP and CHS 828 were both described by one-compartment models. Conclusions: This study illustrates the possibility of measuring antitumour effect, haematological toxicity and pharmacokinetics in the same animal us ing the hollow-fibre model.