The influence of P170-glycoprotein modulators on the efficacy and the distribution of vincristine as well as on MDR1 expression in BRO/mdr1.1 human melanoma xenografts

Multidrug resistance modulators may increase the antitumour efficacy of dru gs affected by P170-glycoprotein (Pgp) in Pgp-positive tumours in vivo. Inh ibition of Pgp function in normal tissues, however, may enhance side-effect s. Dexniguldipine-HCl, its analogues B9203-009 and B9303-036, and the dipyr idamole derivative BIBW22BS could reverse vincristine (VCR) resistance in B RO/mdr1.1 cells (transfected with full-length MDR1 cDNA) and 2780(AD) cells (selected for doxorubicin resistance) in vitro. VCR resistance in BRO/mdr1 .1 xenografts grown subcutaneously (s.c.) in the nude mouse was not or only slightly affected by the Pgp modulators. VCR concentrations in normal mous e tissues increased with the dose of the Pgp modulator administered and thi s was most pronounced in liver, kidney, small gut and colon. Dexniguldipine 40 mg/kg intraperitoneally (i.p.) given once 4 h before VCR 1 mg/kg intrav enously (i.v.) resulted in increased VCR concentrations in BRO/mdr1.1 xenog raft tissue. Surprisingly, when dexniguldipine 40 mg/kg i.p. was administer ed daily x3 before VCR, tumour VCR concentrations were not affected. This p henomenon was not observed in normal mouse tissues. Upregulation of MDR1 mR NA to 2.7- to 3.8-fold higher levels than control mRNA in BRO/mdr1.1 xenogr aft tissue occurred after VCR or dexniguldipine at 4-8 h and up to 1.7-fold at 24-28 h after injection. The combination showed 3.6- to 3.7-fold increa sed levels at 4 h after VCR injection. The lower VCR concentrations measure d in BRO/mdr1.1 xenograft tissue after pretreatment with dexniguldipine for 3 days relative to animals treated with dexniguldipine only once will like ly be caused by a gradual increase of Pgp expression as a response to the u pregulation of MDR1. (C) 1999 Elsevier Science Ltd. All rights reserved.