Abstract
The anti-metabolite chemotherapeutic, gemcitabine is relatively effective for a spectrum of neoplastic conditions that include various forms of leukemia and adenocarcinoma/carcinoma. Rapid systemic deamination of gemcitabine accounts for a brief plasma half-life but its sustained administration is often curtailed by sequelae and chemotherapeutic-resistance. A molecular strategy that diminishes these limitations is the molecular design and synthetic production of covalent gemcitabine immunochemotherapeutics that possess properties of selective “targeted” delivery. The simultaneous dual selective “targeted” delivery of gemcitabine at two separate sites on the external surface membrane of a single cancer cell types represents a therapeutic approach that can increase cytosol chemotherapeutic deposition; prolong chemotherapeutic plasma half-life (reduces administration frequency); minimize innocent exposure of normal tissues and healthy organ systems; and ultimately enhance more rapid and thorough resolution of neoplastic cell populations. Materials and Methods: A light-reactive gemcitabine intermediate synthesized utilizing succinimidyl 4,4-azipentanoate was covalently bound to anti-EGFR or anti-HER2/neu IgG by exposure to UV light (354-nm) resulting in the synthesis of covalent immunochemotherapeutics, gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu]. Cytotoxic anti-neoplastic potency of gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu] between gemcitabine-equivalent concentrations of 10−12 M and 10−6 M was determined utilizing chemotherapeutic-resistant mammary adenocarcinoma (SKRr-3). The organoselenium compound, [Se]-methylselenocysteine was evaluated to determine if it complemented the anti-neoplastic potency of the covalent gemcitabine immunochemotherapeutics. Results: Gemcitabine-(C4-amide)-[anti-EGFR], gemcitabine-(C4-amide)-[anti-HER2/neu] and the dual simultaneous combination of gemcitabine-(C4-amide)-[anti-EGFR] with gemcitabine-(C4-amide)-[anti-HER2/neu] all had anti-neoplastic cytotoxic potency against mammary adenocarcinoma. Gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu] produced progressive increases in anti-neoplastic cytotoxicity that were greatest between gemcitabine-equivalent concentrations of 10−9 M and 10−6 M. Dual simultaneous combinations of gemcitabine-(C4-amide)-[anti-EGFR] with gemcitabine-(C4-amide)-[anti-HER2/neu] produced levels of anti-neoplastic cytotoxicity intermediate between each of the individual covalent gemcitabine immunochemotherapeutics. Total anti-neoplastic cytotoxicity of the dual simultaneous combination of gemcitabine-(C4-amide)-[anti-EGFR] and gemcitabine-(C4-amide)-[anti-HER2/neu] against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) was substantially higher when formulated with [Se]-methylsele-nocysteine.
Highlights
IntroductionMonoclonal immunoglobulin preparations or pharmaceuticals with binding-avidity for HER2/neu (e.g. antiHER2/neu: trastuzumab, pertuzumab), EGFR (e.g. anti-EGFR: cetuximab, gefitinib) [1]-[4], HER2/neu and EGFR (e.g. anti-HER2/neu and anti-EGFR: panitumumab) [3]-[6] IGF-1R, VEGFR and inhibitors of trophic membrane receptors can all potentially be effective treatment options for certain neoplastic conditions including cancer affecting the breast, intestinal tract, lung or prostate
Monoclonal immunoglobulin preparations or pharmaceuticals with binding-avidity for HER2/neu, EGFR [1]-[4], HER2/neu and EGFR [3]-[6] IGF-1R, VEGFR and inhibitors of trophic membrane receptors can all potentially be effective treatment options for certain neoplastic conditions including cancer affecting the breast, intestinal tract, lung or prostate
The objective of the research investigations was to determine if simultaneous selective “targeted” delivery of two covalent gemcitabine immunochemotherapeutics is possible at two different endogenous trophic receptor sites over-expressed on the surface membrane of a neoplastic cell type and establish the potential for [Se]-methylselenocysteine to complement the anti-cancer cytotoxic potency attained with this molecular strategy
Summary
Monoclonal immunoglobulin preparations or pharmaceuticals with binding-avidity for HER2/neu (e.g. antiHER2/neu: trastuzumab, pertuzumab), EGFR (e.g. anti-EGFR: cetuximab, gefitinib) [1]-[4], HER2/neu and EGFR (e.g. anti-HER2/neu and anti-EGFR: panitumumab) [3]-[6] IGF-1R, VEGFR and inhibitors of trophic membrane receptors can all potentially be effective treatment options for certain neoplastic conditions including cancer affecting the breast, intestinal tract, lung or prostate. Based on the increased level of anti-neoplastic cytotoxicity that can potentially be gained through dual simultaneous selectively targeted” epirubicin delivery at trophic receptors over-expressed (EGFR) and highly over-expressed (HER2/neu) by chemotherapeutic resistant mammary adenocarcinoma (SKBr-3) [16] the concept of this molecular strategy does have therapeutic merit. The objective of the research investigations was to determine if simultaneous selective “targeted” delivery of two covalent gemcitabine immunochemotherapeutics is possible at two different endogenous trophic receptor sites over-expressed on the surface membrane of a neoplastic cell type and establish the potential for [Se]-methylselenocysteine to complement the anti-cancer cytotoxic potency attained with this molecular strategy
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