flunarizine and Adenocarcinoma

The potential of the calcium-entry blocker flunarizine in modulating the cytotoxicity of doxorubicin was investigated in human colon-adenocarcinoma cell lines sensitive to (LoVo) or with experimentally induced resistance (LoVo/DX) to doxorubicin. Exposure to 1 to 2 micrograms/ml flunarizine for intervals of up to 24 hr did not affect cell survival in either line. Simultaneous exposure to flunarizine and doxorubicin for 1 hr selectively enhanced doxorubicin activity in the resistant cell line and not in the sensitive cell line. In particular, the doxorubicin concentration able to reduce cell survival by 50% dropped to one third. Moreover, simultaneous exposure to flunarizine significantly increased intracellular doxorubicin accumulation, as evaluated by fluorescence spectrophotometry. Again, flow-cytometric analysis showed hyperpolarization of the membrane in resistant cells, starting from 15 min of exposure to 2 micrograms/ml flunarizine. Finally, in LoVo/DX cells, which normally express gp170, a 24-hr treatment with flunarizine markedly reduced the immunoreactivity of cells with 2 monoclonal antibodies (MAb57 and MRK16) directed against different external epitopes of the glycoprotein. The results from our study indicate the ability of flunarizine to positively modulate doxorubicin-resistance in human colon-adenocarcinoma cells expressing the multidrug-resistance phenotype.

Topics: Adenocarcinoma; Cell Survival; Colonic Neoplasms; Doxorubicin; Drug Resistance, Microbial; Flow Cytometry; Flunarizine; Humans; Membrane Potentials; Neoplasm Proteins; Tumor Cells, Cultured

Flunarizine is a diphenylpiperazine calcium entry blocker that has been shown previously to increase tumor blood flow and sensitivity to radiotherapy via reduction in the radiobiologically significant hypoxic fraction. Two mechanisms of action have been proposed previously (vasodilation, altered blood viscosity), but no studies have been performed to examine its mechanisms of action in vivo. Such information would be invaluable in determining the role of flunarizine in multimodality approaches to reduce tumor hypoxia. Fisher-344 rats bearing R3230Ac tumors transplanted into dorsal flap window chambers were used to examine microcirculatory changes after administration of flunarizine (1.0 mg/kg, iv). The drug increased the diameters of the microvasculature and red cell velocities specifically in central tumor regions (producing an average increase in vessel flow by a factor of 1.96), which was accompanied by an increase in perivascular pO2 of 12 mm Hg, on the average. The drug did not change the diameters of tumor "feeding" vessels, nor did it change vascular length densities. Thus the improvement in central tumor blood flow and oxygenation could not be attributed to dilation of feeding vessels. The oxygen-carrying capacity of the blood was not altered either since hemoglobin saturation (measured in vitro) and the hematocrits of the microvasculature were unchanged after drug administration. Therefore, by a process of elimination, the most likely explanation for the effect of the drug is modification of blood viscosity. Additional studies are under way in this laboratory to examine whether changes in viscosity occur after flunarizine administration.

Topics: Adenocarcinoma; Animals; Flunarizine; Hemodynamics; Mammary Neoplasms, Experimental; Microcirculation; Neoplasm Transplantation; Oxygen Consumption; Rats; Rats, Inbred F344

Tumor blood flow is an important determinant of the efficacy of presently available antineoplastic treatment modalities. Using 113Sn-labeled microspheres, 25 micron in diameter, we measured blood flow to primary tumors and regional lymph node metastases in conscious SMT-2A mammary adenocarcinoma-bearing syngeneic rats following a single i.v. bolus injection of the calcium entry blocker, flunarizine. Tumor blood flow increased in a biphasic dose-dependent fashion; at a dose of 1 mg/kg, primary tumor blood flow increased approximately 50% (p less than 0.001) without a significant change in heart rate or blood pressure. The increase in flow was distributed to both the peripheral viable and central necrotic regions of the tumor and was still detectable 45 min following administration of the drug. A similar increase in blood flow was demonstrated for lymph node metastases (p less than 0.001).

Topics: Adenocarcinoma; Animals; Calcium Channel Blockers; Cinnarizine; Female; Flunarizine; Kinetics; Lymphatic Metastasis; Mammary Neoplasms, Experimental; Organ Specificity; Piperazines; Rats; Rats, Inbred Strains; Regional Blood Flow