dihydropyridines and Adenocarcinoma

The pharmacokinetics of oral dexniguldipine, a new multidrug-resistance-modifying agent under clinical evaluation, and its pyridine metabolite M-1 were determined in plasma, tumor, and renal tissue in Wag/Rij rats bearing a multidrug-resistant CC531 colon adenocarcinoma tumor under the renal capsule. The pharmacokinetics were studied in four experiments. After a single administration of dexniguldipine (30 mg/kg), tumors and kidneys were collected after 5 (experiment 1), 24 (experiment 2), and 48 h (experiment 3). In the fourth experiment, dexniguldipine was given once daily for 3 consecutive days at a dose of 30 mg/kg. In all experiments, plasma samples were collected at regular intervals. The concentrations of dexniguldipine and M-1 could be determined in plasma in most of the rats at up to 32 h after drug administration. The area under the curve (AUC) of dexniguldipine and M-1 varied by a factor of 2-6 in the four experiments. High tumor-tissue concentrations of dexniguldipine were observed. The concentrations were highest in the multiple-dose experiment (2014 +/- 1005 ng/g tissue). High degrees of correlation (> 0.8) were established between the concentrations of dexniguldipine measured in plasma and tumor as well as renal tissue. Overall, tumor-tissue concentrations of M-1 comprised one-third of the dexniguldipine concentrations measured.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Colonic Neoplasms; Dihydropyridines; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Kidney; Neoplasm Transplantation; Pyridines; Rats; Rats, Inbred Strains

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.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Biotransformation; Colonic Neoplasms; Dihydropyridines; Drug Resistance, Multiple; Drug Screening Assays, Antitumor; Drug Synergism; Epirubicin; Male; Neoplasm Transplantation; Rats; Rats, Inbred Strains; Tumor Cells, Cultured

Two new dihydropyridine derivatives with low calcium channel affinity, S16317 and S16324, were found to fully overcome multidrug resistance in vitro. These two compounds increased doxorubicin cytotoxicity on the human COLO 320DM cell line and completely reversed the vincristine resistance of murine P388/VCR cells. In vivo, S16324 administered p.o. (200 mg/kg on days 1 to 4) or i.p. (50 mg/kg on days 1, 5, 9) in combination with vincristine (i.p.) restored the antitumor activity of vincristine in P388/VCR-bearing mice. S16317 showed a reversing activity when administered p.o., i.v. (days 1 to 4) or i.p. (days 1, 5, 9) at the same dose (25 mg/kg), suggesting a remarkable bioavailability. Moreover, these two compounds potentiated the antitumor activity of vincristine in the sensitive P388 leukemia, increasing the number of long-term survivors. These results suggest that combination chemotherapy using S16317 or S16324 would be effective not only in circumventing multidrug resistance but also in preventing the emergency of a population of resistant tumor cells in sensitive tumors.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Calcium Channels; Colonic Neoplasms; Dihydropyridines; Doxorubicin; Drug Resistance, Multiple; Drug Screening Assays, Antitumor; Drug Synergism; Felodipine; Female; Humans; Leukemia P388; Mice; Mice, Inbred DBA; Neoplasm Transplantation; Tumor Cells, Cultured; Vincristine

The dihydropyridine, dexniguldipine hydrochloride (B859-35), has shown therapeutic activity in experimentally induced neuroendocrine hamster lung tumors and demonstrated antiproliferative effects in a mammary cancer cell line via inhibition of Ca2+ calmodulin. Studies in NIH 3T3 fibroblasts have provided evidence that dexniguldipine may also inhibit protein kinase C (PKC). In this study, we have tested the hypothesis that dexniguldipine may inhibit the proliferation of lung cancer cells in response to autocrine or exogenous activation of PKC. Using a panel of human lung cancer cell lines, we show that dexniguldipine is a potent inhibitor of mitogenic signal transduction pathways dependent on PKC activation in several small-cell and non-small-cell lung cancer cell lines while it failed to inhibit cyclic-AMP-dependent cell proliferation.

Topics: Adenocarcinoma; Antineoplastic Agents; Carcinoid Tumor; Carcinoma, Adenosquamous; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Division; Dihydropyridines; Humans; Lung Neoplasms; Protein Kinase C; Tumor Cells, Cultured

A new triazinoaminopiperidine derivative, Servier 9788 (S9788), was investigated for its ability to increase Adriamycin (ADR) accumulation and retention in two rodent (P388/ADR and DC-3F/AD) and three human (KB-A1, K562/R and COLO 320DM) cell lines displaying the P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) phenotype. Depending on the cell line S9788 was shown to be two to five times more active and five to 15 times more potent than Verapamil (VRP) in increasing ADR accumulation in resistant cells. ADR retention in KB-A1 cells maintained in a concentration of 10 microM S9788 was twice that in VRP-treated cells, and similar to that measured in the untreated sensitive KB-3-1 cells. Although 5 microM S9788 and 50 microM VRP gave the same values of ADR uptake in KB-A1 cells, S9788 was shown to induce a greater ADR retention following cell wash and post-incubation in resistance modifier- and ADR-free medium. Taking into account that S9788 had no effects on ADR accumulation and retention in sensitive KB-3-1 cells, it can be suggested that S9788 inhibits specifically the P-gp dependent ADR efflux, and in a manner less reversible than that observed with VRP. Moreover, [3H]azidopine photolabeling of P-gp, in P388/ADR plasma membranes, was completely inhibited by 100 microM S9788. Although S9788, as VRP, had no effect on the cell cycle of P388 cells, 5 microM S9788 increased 700-fold the efficacy of ADR to block P388/ADR cells in the G2+M phase of the cell cycle. Together, these results show that the sensitization, by S9788, of cell lines resistant to ADR is mainly due to an increase in ADR accumulation and retention, leading to an increase in the number of resistant cells blocked in the G2+M phase.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Azides; Carcinoma, Squamous Cell; Cell Cycle; Cell Membrane; Cells, Cultured; Colonic Neoplasms; Cricetinae; Cricetulus; Dihydropyridines; Doxorubicin; Drug Resistance; Flow Cytometry; Fluorescence; Humans; Kinetics; Leukemia P388; Leukemia, Myeloid, Acute; Lung; Membrane Glycoproteins; Mice; Piperidines; Sensitivity and Specificity; Triazines; Tritium; Tumor Cells, Cultured; Verapamil

We have recently demonstrated that the dihydropyridine-derivative B859-35 has a selective chemotherapeutic effect on experimentally induced neuroendocrine lung tumors in hamsters. These tumors resembled human atypical lung carcinoids morphologically and expressed mammalian bombesin, calcitonin and neuron-specific enolase. In the hamster model, B859-35 had no antiproliferative effect on pulmonary adenomas of Clara cell origin. In this study, we have tested the antiproliferative effects of B859-35 and of the Ca(2+)-channel blocker Verapamil in vitro on three human lung cancer cell lines. The neuroendocrine cell line NCI-H727 is derived from a lung carcinoid and expresses mammalian bombesin and calcitonin. Two non-neuroendocrine cell lines are derived from peripheral pulmonary adenocarcinomas, with line NCI-H322 expressing features of Clara cells while line NCI-H358 expresses features of alveolar type II cells. B859-35 was a potent antiproliferative agent in the neuroendocrine line NCI-H727 at concentrations as low as 0.001 pM, while it inhibited cell proliferation in the two other cell lines at concentrations of 100 nM and above. Verapamil inhibited cell proliferation in the neuroendocrine line NCI-H727 at concentrations of 1 nM and above.

Topics: Adenocarcinoma; Antineoplastic Agents; Calcium Channel Blockers; Carcinoid Tumor; Cell Division; Dihydropyridines; Humans; Lung Neoplasms; Tumor Cells, Cultured; Verapamil