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 drugs affected by P170-glycoprotein (Pgp) in Pgp-positive tumours in vivo. Inhibition of Pgp function in normal tissues, however, may enhance side-effects. Dexniguldipine-HCl, its analogues B9203-009 and B9303-036, and the dipyridamole derivative BIBW22BS could reverse vincristine (VCR) resistance in BRO/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 mouse tissues increased with the dose of the Pgp modulator administered and this 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 intravenously (i.v.) resulted in increased VCR concentrations in BRO/mdr1.1 xenograft tissue. Surprisingly, when dexniguldipine 40 mg/kg i.p. was administered daily ×3 before VCR, tumour VCR concentrations were not affected. This phenomenon was not observed in normal mouse tissues. Upregulation of MDR1 mRNA to 2.7- to 3.8-fold higher levels than control mRNA in BRO/mdr1.1 xenograft 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 increased levels at 4 h after VCR injection. The lower VCR concentrations measured in BRO/mdr1.1 xenograft tissue after pretreatment with dexniguldipine for 3 days relative to animals treated with dexniguldipine only once will likely be caused by a gradual increase of Pgp expression as a response to the upregulation of MDR1.