Modulation of multidrug resistance with dexniguldipine hydrochloride (B8509-035) in the CC531 rat colon carcinoma model.
The chemosensitizing potency of dexniguldipine hydrochloride (B8509-035) on epidoxorubicin was assessed in a multidrug-resistant (MDR) tumour model, the intrinsic MDR rat colon carcinoma CC531. In vitro in the sulphorhodamine B cell-viability assay the cytotoxicity of epidoxorubicin was increased approximately 15-fold by co-incubation with 50 ng/ml dexniguldipine. In vivo concentrations of dexniguldipine 5 h after a single oral dose of 30 mg/kg were 72 (+/- 19 SD) ng/ml in plasma and 925 (+/- 495 SD) ng/g in tumour tissue. Levels of the metabolite of dexniguldipine, M-1, which has the same chemosensitizing potential, were 26 (+/- 6 SD) ng/ml and 289 (+/- 127 SD) ng/g respectively. The efficacy of treatment with 6 mg/kg epidoxorubicin applied intravenously combined with 30 mg kg-1 day-1 dexniguldipine administered orally for 3 days prior to epidoxorubicin injection was evaluated on tumours grown under the renal capsule. Dexniguldipine alone did not show antitumour effects in vivo. Dexniguldipine modestly, but consistently, potentiated the tumour-growth-inhibiting effect of epidoxorubicin, reaching statistical significance in two out of four experiments. In conclusion, these experiments show that dexniguldipine has potency as an MDR reverter in vitro and in vivo in this solid MDR tumour model.
Van de Vrie
W
W
Department of Surgical Oncology, Rotterdam Cancer Institute, The Netherlands.
Schellens
J H
JH
Loss
W J
WJ
Kolker
H J
HJ
Verwey
J
J
Stoter
G
G
Durante
N M
NM
Eggermont
A M
AM
D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D003110:Colonic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004095:Dihydropyridines / Q000008:administration & dosage / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D015251:Epirubicin / Q000008:administration & dosage; D008297:Male; D009368:Neoplasm Transplantation; D051381:Rats; D011919:Rats, Inbred Strains; D014407:Tumor Cells, Cultured
D004095:Dihydropyridines; D015251:Epirubicin; C054074:niguldipine