flunarizine and Ovarian-Neoplasms

The epithelial glycoprotein 40 (EGP40) is an important target in the clinic for radioimmunolocalization and monoclonal antibody (MAb)-mediated therapy of cancer. We determined which tumor-related factors (including antigen distribution and density, vascularization and perfusion) were involved in the uptake of the anti-EGP40 MAb 323/A3 in 4 different human ovarian cancer xenografts grown s.c. in nude mice. The reactivity pattern of 323/A3 in all xenografts in vitro was similar and showed a strong and homogeneous distribution of the EGP40 antigen. FMa xenografts, however, showed the highest uptake of 323/A3 in vivo, which was 5.5-, 6.2- and 10.0-fold higher than that in OVCAR-3, Ov.Pe and Ov.Sh xenografts, respectively. FMa xenografts contained 2.1- to 3.5-fold more antigen per gram protein when compared with the antigen content of the other xenografts. FMa and Ov.Sh xenografts demonstrated a better vascularization pattern, whereas Ov.Pe and OVCAR-3 xenografts were moderately to poorly vascularized. FMa xenografts were also better perfused, as was shown by a 1.6- to 1.8-fold higher uptake of the (99m)Tc-labeled blood flow marker hexamethylpropyleneamine oxime (HMPAO). The tumor uptake of the non-specific MAb E48 was 2.2- to 11.2-fold lower when compared with that of 323/A3, but the sequence of uptake was similar (FMa > OVCAR-3 = Ov.Pe > Ov.Sh), indicating the lowest extravasation of MAbs in Ov.Sh xenograft tissue. Since both the antigen content and the perfusion appeared to be important factors of influence on the tumor uptake of 323/A3, attempts were made to manipulate these determinants to improve the tumor uptake. Neither gamma-interferon nor 5-fluorouracil were able to increase EGP40 expression in human ovarian cancer cells in vitro. Treatment of tumor-bearing mice with the calcium-antagonist flunarizine did not result in an improved perfusion, although a slight increase in the initial tumor uptake of 323/A3 was observed in Ov.Sh-bearing mice. Our results illustrate the relative contribution of various tumor-related factors that determine the usefulness of a MAb for imaging and therapy of cancer.

Topics: Animals; Antibodies, Monoclonal; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoembryonic Antigen; Cell Adhesion Molecules; Colorectal Neoplasms; Epithelial Cell Adhesion Molecule; Female; Flunarizine; Fluorouracil; Genes, MHC Class I; Humans; Hypopharyngeal Neoplasms; Immunohistochemistry; Interferon-gamma; Mice; Mice, Nude; Neoplasm Transplantation; Ovarian Neoplasms; Radionuclide Imaging; Recombinant Proteins; Tissue Distribution; Tumor Cells, Cultured

We investigated the effect of pharmacological modulators on the cytotoxic activity of melphalan and cisplatin in human ovarian cystadenocarcinoma cells sensitive (OAW42) or resistant (OAW42MER) to bifunctional alkylating agents. By filter elution experiments we observed a reduced accumulation and a faster repair of melphalan-induced DNA interstrand cross-links in the OAW42MER resistant cells than in the OAW42 parental, sensitive cells. Moreover, resistant cells were characterized by an increased level of mRNA encoding enzymes involved in the nucleotide excision repair pathway, such as ERCC (excision repair cross complementing)1 and ERCC2. Among the modulators used, the topoisomerase I inhibitor topotecan was able to increase melphalan cytotoxic activity in sensitive and resistant cell lines. Topotecan also positively modulated cisplatin activity, although to a variable extent in the two cell lines, as a function of treatment schedule. The energolytic compound lonidamine markedly enhanced the cytotoxicity of melphalan and cisplatin, with a potentiating effect in the OAW42MER resistant cells almost 2-fold that of in the OAW42 sensitive cells. No significant potentiation was observed by using calcium channel blockers, such as verapamil and nimodipine. Conversely, an increase in melphalan cytotoxic activity was determined by flunarizine in OAW42MER resistant cells and, to a lesser extent, in OAW42 sensitive cells. However, the calcium blocker failed to modulate cisplatin activity in both cell lines.

Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Blotting, Northern; Calcium Channel Blockers; Cell Survival; Cisplatin; Culture Media; Cystadenoma; Drug Resistance, Neoplasm; Female; Flunarizine; Humans; Melphalan; Nimodipine; Ovarian Neoplasms; RNA Probes; RNA, Neoplasm; Tumor Cells, Cultured; Verapamil