Determination of drug effect on tumour cells, host animal toxicity and drug pharmacokinetics in a hollow-fibre model in rats.
OBJECTIVE
Based on the previously published hollow-fibre assay mainly used for early in vivo anticancer drug screening, we wanted to develop an extended hollow-fibre model in which antitumour activity, haematological toxicity and pharmacokinetics could be studied in the same animal.


METHODS
The breast cancer cell lines MDA-MB-231 and MCF-7 were cultured in semipermeable hollow fibres. The fibres were implanted subcutaneously into immunocompetent male 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 and two to four samples per animal were drawn to determine the pharmacokinetic 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 exerted a statistically significant antiproliferative effect. CHS 828 had only 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 seem to affect these parameters. The pharmacokinetics of 5-FU and EPI were in accordance with previously established pharmacokinetic models. The pharmacokinetics 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 using the hollow-fibre model.
Jonsson
E
E
Division of Clinical Pharmacology, Akademiska Hospital, SE-751 85 Uppsala, Sweden. elin.jonsson@medsci.uu.se
Friberg
L E
LE
Karlsson
M O
MO
Hassan
S B
SB
Freijs
A
A
Hansen
K
K
Larsson
R
R
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D002452:Cell Count; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003520:Cyclophosphamide / Q000009:adverse effects / Q000493:pharmacokinetics; D004354:Drug Screening Assays, Antitumor; D015251:Epirubicin / Q000009:adverse effects / Q000493:pharmacokinetics; D005472:Fluorouracil / Q000009:adverse effects / Q000493:pharmacokinetics; D007108:Immune Tolerance; D008297:Male; D023421:Models, Animal; D019736:Prostheses and Implants; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured
D015251:Epirubicin; D003520:Cyclophosphamide; D005472:Fluorouracil