title: Pharmacology and antitumour effects of intraportal pirarubicin on experimental liver metastases.
abstract: Early liver metastases have a predominant portal blood supply. Intraportal (i.port.) vein administration of cytotoxics could theoretically achieve enhanced drug concentrations in tumour cells and be effective as adjuvant therapy after resection of colorectal carcinoma. Pirarubicin (which has a higher hepatic extraction than doxorubicin) was investigated on liver metastases of the VX2 rabbit tumour, which were of less than 2 mm in diameter 7 days after cells injection into the portal vein. To evaluate antitumour activity, 24 rabbits were randomised into three groups 7 days after implantation: (a) control, (b) i.v. pirarubicin, (c) i.port. pirarubicin at doses of 2 mg kg-1 in both groups. Portal infusions led to no hematological or hepatic toxicity. Pharmacokinetic parameters showed a significantly reduced systemic exposure after i.port. administration. Fourteen days after treatment, livers and lungs were analysed. The mean number (+/- s.d.) of tumour foci was (a) 8.62 (+/- 5.4), (b) 4.62 (+/- 3.2), (c) 2.25 (+/- 1.4) (P < 0.05 a vs c). The mean tumour area was (a) 6.31 (+/- 6.1), (b) 1.31 (+/- 2.2), (c) 0.43 (+/- 0.4 cm2) (P < 0.05 a vs c) and the percentage (95% C.I.) of rabbits with lung metastasis was: (a) 87.5% (47-99%), (b) 75% (35-97%), (c) 12.5% (3-52%) (P < 0.02 b vs c). Intraportal pirarubicin seems to be well tolerated and more efficient than i.v. administration, particularly in preventing extrahepatic dissemination.
authors.affiliation: Département de Médecine, Institut Gustave-Roussy, Villejuif, France.
authors.forename: L H
authors.initials: LH
authors.lastname: Ramirez
authors.forename: J N
authors.initials: JN
authors.lastname: Munck
authors.forename: C
authors.initials: C
authors.lastname: Bognel
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
authors.forename: P
authors.initials: P
authors.lastname: Ardouin
authors.forename: M F
authors.initials: MF
authors.lastname: Poupon
authors.forename: A
authors.initials: A
authors.lastname: Gouyette
authors.forename: P
authors.initials: P
authors.lastname: Rougier
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D007262:Infusions, Intravenous; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D011169:Portal Vein; D011817:Rabbits
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; C027260:pirarubicin