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Modulation of multidrug resistance with dexniguldipine hydrochloride (B8509-035) in the CC531 rat colon carcinoma
W Van de Vrie1, J H Schellens, W J Loss
1Department of Surgical Oncology, Rotterdam Cancer Institute, The Netherlands.
Abstract:
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.
Insights
Dexniguldipine hydrochloride enhances epidoxorubicin
Area of Science:
- Pharmacology
- Oncology
- Drug Discovery
Background:
- Multidrug resistance (MDR) is a major challenge in cancer chemotherapy.
- Identifying effective MDR modulators is crucial for improving treatment outcomes.
Purpose of the Study:
- To evaluate the chemosensitizing potential of dexniguldipine hydrochloride on epidoxorubicin in a rat colon carcinoma model.
- To assess the in vitro and in vivo efficacy of dexniguldipine as a multidrug resistance reverter.
Main Methods:
- In vitro cytotoxicity assessed using the sulphorhodamine B cell-viability assay.
- In vivo studies utilized a rat colon carcinoma CC531 MDR tumor model with dexniguldipine and epidoxorubicin treatment.
- Drug and metabolite concentrations measured in plasma and tumor tissue.
Main Results:
- Dexniguldipine increased epidoxorubicin cytotoxicity approximately 15-fold in vitro.
- In vivo, dexniguldipine administration led to significant drug and metabolite levels in plasma and tumor tissue.
- Combined treatment showed modest but consistent potentiation of epidoxorubicin's tumor-growth-inhibiting effect.
Conclusions:
- Dexniguldipine hydrochloride demonstrates significant potency as an MDR reverter in vitro.
- The drug also shows in vivo efficacy in reversing multidrug resistance in a solid tumor model.
- These findings suggest dexniguldipine's potential in overcoming chemotherapy resistance.