Influence of Alternative Tubulin Inhibitors on the Potency of Epirubicin-Immunochemotherapeutic Synthesized with an Ultra Violet Light-Activated Intermediate

Abstract

-10 M and 10 -6 M was determined by measuring the vitality/proliferation of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3 cell type). Cytotoxic anti-neoplastic potency of benzimidazoles (albendazole, flubendazole, membendazole) and griseofulvin were assessed between 0-to-2 g/ml and 0-to-100 g/ml respectively while mebendazole and griseofulvin were analyzed at fixed concentrations of 0.35 g/ml and 35 g/ml respectively in dual combination with gradient concentrations of epirubicin-(C 3 -amide)-[anti-HER2/neu] and epirubicin-(C 3 -amide)-SS-[anti-HER2/neu].Cytotoxic anti-neoplastic potency for epirubicin-(C 3 -amide)-[anti-HER2/neu] and epirubicin-(C 3 -amide)-SS-[anti-HER2/neu] against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) was nearly identical at epirubicin-equivalent concentrations of 10 -10 M and 10 -6 M. The benzimadazoles also possessed cytotoxic anti-neoplastic activity with flubendazole and albendazole being the most and least potent respectively. Similarly, griseofulvin had cytotoxic anti-neoplastic activity and was more potent than methylselenocysteine. Both mebendazole and griseofulvin when applied in dual combination with either epirubicin-(C 3 -amide)-[anti-HER2/neu] or epirubicin-(C 3 -amide)-SS-[anti-HER2/neu] produced enhanced levels of cytotoxic anti-neoplatic potency.

Gemcitabine-(C4-amide)-[anti-HER2/neu] Anti-Neoplastic Cytotoxicty in Dual Combination with Mebendazole against Chemotherapeutic-Resistant Mammary Adenocarcinoma

“…Flubendazole was the most potent benzimidazole while albendazole was substantially less potent than either flubendazole or mebendazole against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) at benzimidazole-equivalent concentrations below 0.75 mM (Figures 6 and 7). The relative order of benzimidazole cytotoxic anti-neoplastic potency against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) closely correlates with profiles recognized with other neoplastic cell types including leukemia [89] and myeloma [89] cell types at longer incubation periods (Figures 6 and 7) [40,41]. …”

“…In direct correlation with these findings, benzimidazoles also (additively or synergistically) complement the cytotoxic anti-neo-plastic potency of epirubicin and covalent epirubicin immunoche-motherapeutics against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) [41]. Undoubtedly, levels of cytotoxic anti-neoplastic potency for gemcitabine-(C 4 - amide )-[anti-HER2/ neu ] immunochemotherapetuic in dual combination with mebendazole (0.15 μM fixed-concentration) would probably be measurably greater with the implementation of direct-contact incubation periods longer than 182-hours.…”

“…Gemcitabine-(C 4 - amide )-[anti-HER2/ neu ] at the gemcitabine-equivalent concentrations of 10 -7 M or 10 -6 M during a 182-hour incubation period did not exert a substantially greater degree of selectively “targeted” anti-neoplastic potency against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) compared to gemcitabine alone (Figures 4, 9 and 10). Such findings are in contrast to the measurably greater or equivalent levels of cytotoxic anti-neoplastic potency of covalent epirubicin-[anti-HER2/ neu ] immunochemotherapeutics compared to epirubicin alone [41-44]. Despite this diference, results imply that greater levels of selectively “ targeted ” cytotoxic anti-neoplastic potency could have been attained with gemcitabine-(C 4 - amide )-[anti-HER2/ neu ] at incubation periods of duration greater than 182-hours (Figure 4).…”

Anti-Neoplastic Cytotoxicity of Gemcitabine-(C4-amide)-[anti-EGFR] in Dual-combination with Epirubicin-(C3-amide)-[anti-HER2/neu] against Chemotherapeutic-Resistant Mammary Adenocarcinoma (SKBr-3) and the Complementary Effect of Mebendazole

“…Alternatively it is assumed that inhibiting the function of two different trophic receptors that each have essentially an identical influence or effect on cancer cell biology would probably not produce a synergistic effect but could promote greater suppression of neoplastic cell vitality and proliferation than is possible with just a single anti-trophic receptor immunoglobulin. Although the in-vivo immune-mediated anti-neoplastic properties of anti-trophic receptor immunoglobulins is highly relevant, such processes are unfortunately challenging to collectively simulate and difficult accurately detect during the relatively brief incubation periods employed for evaluating the ex-vivo potency of many if not most covalent immunochemotherapeutics[ 66 , 85 , 97 – 99 , 102 , 160 ].…”

“…7 ). Such findings correlate with mebendazole additively or synergistically contributing to the anti-neoplastic cytotoxicity of epirubicin-(C 3 - amide )-[anti-HER2/ neu ][ 160 ] and gemcitabine-(C 4 - amide )-[anti-HER2/ neu ][ 99 ]. Preliminary experimental investigations have detected vulnerability of adrenocortical carcinoma (xenographs),[ 180 ] colorectal cancer,[ 181 , 182 ] hepatocellular carcinoma,[ 182 , 183 ] leukemia,[ 184 , 185 ] lung cancer,[ 186 ] (non-small cell[ 186 , 187 ]), melanoma (chemo-resistant),[ 188 ] myeloma,[ 185 ] and ovarian cancer,[ 183 , 189 – 191 ] to benzimidazole tubulin/microtubule inhibitors.…”