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Anti-HER2/Neu Journal of Cancer Therapy, 2011, 2, 22-39 doi:10.4236/jct.2011.21004 Published Online March 2011 (http://www.SciRP.org/journal/jct) Epirubicin-[Anti-HER2/neu] Synthesized with an Epirubicin-(C13-imino)-EMCS Analog: Anti-Neoplastic Activity against Chemotherapeutic-Resistant SKBr-3 Mammary Carcinoma in Combination with Organic Selenium Cody P. Coyne1, Toni Jones1, Andrzej Sygula2, John Bailey3, Lesya Pinchuk1 1Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, USA; 2Department Organic Chemistry, Mississippi State University, Mississippi State, USA; 3College of Osteopathic Medicine, William Cary Univer- sity, Hattiesburg, USA. Email: [email protected] Received October 16th, 2010; revised December 10th, 2010; accepted 17th, 2010. ABSTRACT Purpose: Discover the anti-neoplastic efficacy of epirubicin-(C13-imino)-[anti-HER2/neu] against chemotherapeutic- resistant SKBr-3 mammary carcinoma and delineate the capacity of selenium to enhance it’s cytotoxic anti-neoplastic potency. Methods: In molar excess, EMCH was combined with epirubicin to create a covalent epirubicin-(C13-imino)- EMCH-maleimide intermediate with sulfhydryl-reactive properties. Monoclonal immunoglobulin selective for HER2/neu was then thiolated with 2-iminothiolane at the terminal ε-amine group of lysine residues. The sulfhydryl-reactive epiru- bicin-(C13-imino)-EMCH intermediate was then combined with thiolated anti-HER2/neu monoclonal immunoglobulin. Western-blot analysis was utilized to characterize the molecular weight profiles while binding of epirubicin-(C13-imino)- [anti-HER2/neu] to membrane receptors was determined by cell-ELISA utilizing populations of SKBr-3 mammary car- cinoma that highly over-expresses HER2/neu complexes. Anti-neoplastic potency of epirubicin-(C13-imino)-[anti-HER2/ neu] between the epirubicin-equivalent concentrations of 10–12 M and 10–7 M was determined by vitality staining analy- sis with and without the presence of selenium (5 μM). Results: Epiribucin-(C13-imino)-[anti-HER2/neu] between epiru- bicin-equivalent concentrations of 10–8 M to 10–7 M consistently evoked higher anti-neoplastic potency than “free” non- conjugated epirubicin which corresponded with previous investigations utilizing epirubicin-(C3-amide)-[anti-HER2/neu] and epirubicin-(C3-amide)-[anti-EGFR]. Selenium at 5 mM consistently enhanced the cytotoxic anti-neoplastic potency of epirubicin-(C13-imino)-[anti-HER2/neu] at epirubicin equivalent concentrations (10–12 to 10–7 M). Conclusions: Epirubicin-(C13-imino)-[anti-HER2/neu] is more potent than epirubicin against chemotherapeutic-resistant SKBr-3 mammary carcinoma and selenium enhances epirubicin-(C13-imino)-[anti-HER2/neu] potency. The methodology ap- plied for synthesizing epirubicin-(C13-imino)-[anti-HER2/neu] is relatively time convenient and has low instrumentation requirements. Keywords: Epirubicin-(C13-Imino)-[Anti-HER2/neu], Chemotherapeutic-Resistant Mammary Carcinoma, HER2/neu, Selenium, Synthesis 1. Introduction immunoglobulin-based therapeutics of this type report- edly have an inability to exert significant cytotoxic activ- Monoclonal immunoglobulin fractions with binding ity or completely resolve neoplastic conditions [1-7] avidity for HER2/neu and EGFR have demonstrated ef- unless they are applied in combination with chemother- fectiveness in the treatment of mammary carcinoma and apy or other forms of anti-cancer treatment [8,9]. Despite other neoplastic disease states that over-express these general familiarity with the influence of anti-HER2/neu trophic membrane-associated receptors. Unfortunately, immunoglobulin on cancer cell biology and its applica- Copyright © 2011 SciRes. JCT Epirubicin-[Anti-HER2/neu] Synthesized with an Epirubicin-(C13 -imino)-EMCS Analog: Anti-Neoplastic Activity 23 Against Chemotherapeutic-Resistant SKBr-3 Mammary Carcinoma in Combination with Organic Selenium tion in clinical oncology there is surprisingly little known immunoglobulin (e.g. BR96/SGN15) [32-35] in part be- about covalent anthracycline-[anti-HER2/neu] immuno- cause it has cross-cancer-efficacy against lung carcinoma chemotherapeutics and their potential to exert enhanced [32,35,36], intestinal carcinoma [32-34,37], and ovarian levels of anti-neoplastic activity against chemotherapeu- carcinoma [33]. The full anti-neoplastic efficacy of co- tic-resistant mammary carcinoma [10]. valent epirubicin-(C13-imino)-[anti-HER2/neu] immuno- A small collection of organic chemistry reactions can chemotherapeutics proportedly increased through en- be used to covalently link anthracycline-class chemo- hanced acid-sensitive mediated liberation of the anthra- therapeutic agents to monoclonal immunoglobulin or cycline within the micro-environment of the phagoly- other biologically active protein fractions. One common sosome/endolysosome (pH 5.0 - 5.5) remains to be de- methodology for the synthesis of anthracycline conju- lineated. Similarly, although previous investigations have gates involves the creation of a covalent amide bond at characterized the influence of selenium on the biology of the single C3 α-monoamine group of the anthracycline various neoplastic cell type, little is know about the po- carbohydrate moiety [10-13]. Dual combinations of tential for selenium to enhance the cytotoxiic anti-neo- epirubicin-(C3-amide)-[anti-HER2/neu] and epirubicin- plastic potency of epirubicin-(C13-imino)-[anti-HER2/neu] (C3-amide)-[anti-EGFR] have demonstrated synergistic against chemotherapeutic-resistant mammary carcinoma. levels of anti-neoplastic activity against chemotherapeu- tic-resistant SKBr-3 mammary carcinoma which is com- 2. Materials and Methods plemented by the simultaneous application of competi- 2.1. Synthesis Methodology I: Epirubicin- tive P-glyco-protein inhibitors [10]. (C13-keto)-EMCH-Immunoglobulin Generation of an imino covalent bond at the C13-keto group of anthracyclines utilizing reactive hydrazides is Phase-I: Immunoglobulin Thiolation at Lysine ε-Amine an alternative synthesis strategy [14-18]. Chemically Groups-A purified fraction of monoclonal immunoglobu- lin with binding-avidity specifically for human HER2/neu reactive anthracycline (C13-imino) intermediates pro- duced in this manner have been applied to synthesize a (ErbB-2, CD 340) was utilized for the semi-synthesis of variety of composite chemotherapeutic preparations epirubicin-(C13-imino)-[anti-HER2/neu]. Dessicated anti- through the formation of a secondary covalent bond to a HER2/neu monoclonal immunoglobulin (1.5 mg) was variety of ligands and carrier molecules including HPMA combined with 2-iminothiolane (2-IT: 6.5 mM final con- (N-(2-hydroxy-propyl)-methacrylamide) [19,20], poly- centration) in PBS (0.1 M, pH 8.0, 250 μl) and incubated ethylene glycol (PEG) [21], DNA aptamer [22], trans- at 25˚C for 1.5 hours in combination with simultaneous ferin [23,24], albumin/lactosaminated albumin [14,15]. constant gentle stirring [11,38-40]. Thiolated anti-HER2/ Similarly, doxorubicin-EMCH derivatives with a sulfhy- neu monoclonal immunoglobulin was then buffer ex- dryl-reactive maleimide moiety (e.g. DOXO-EMCH) changed into PBS-EDTA (phosphate 0.1, NaCl 0.15 M, have been synthesized which form conjugates with serum EDTA 10 mM, pH 7.3) using micro-scale column chro- albumin following intravenous administration and are matography. Moles of reduced sulfhydryl groups cova- subsequently internalized by certain neoplastic cell types lently introduced into anti-HER2/neu monoclonal im- [16,25,26]. munoglobulin was measured with a 5,5’-dithiobis-(2- Immunochemotherapeutics synthesized through the nitrobenzoic acid (DTNB reagent) based assay. The av- creation of a covalent imino bond at the C13-keto group erage number of thiolated lysine ε-amine groups intro- of anthracyclines have been described [27-29] utilizing duced into anti-HER2/neu fractions (R-SH/IgG) was 3:1 only a rather limited spectrum of monocloncal immu- using 2-IT reagent. noglobulin fractions. Furthermore, in contrast to immu- Phase-II: Synthesis of Epirubicin-(C13-imino)-EMCH noglobulin-based diagnostic radiopharmaceuticals and Sulfhydryl Reactive Intermediate-The C13-keto group of radioimmunotherapeutics, there are few descriptions of epirubicin (1.479 × 10–2 mg, 2.55 × 10–5 mMole in the molecular design, synthesis and efficacy evaluation methanol) was reacted with the hydrazide group of the of covalent anthracycline immunochemotherapeutics that heterobifunctional covalent cross-linking reagent, N-ε- exert selective anti-neoplastic properties against mam- maleimi-docaproic acid hydrazide in the presence of mary carcinoma propagated in-vitro in tissue culture trifluoroacetic acid (EMCH: 43.2 μg, 1.275 × 10–4 mmol [30,31], in-vivo xenografts [32], or natural clinical dis- in methanol) and then incubated at 25˚C for 96 hours in ease states. Immunochemotherapeutics synthesized as concert with constant gentle stirring [17,24]. Recrystali- anthracycline (C13-imino)-immunoglobulin with selective zation of epirubicin-(C13-imino)-EMCH to remove re- “targeted” delivery properties for breast cancer have sidual unreacted EMCH was performed by the addition predominately utilized anti-Lewis Y antigen monoclonal of acetonitrile until a slight opalescent appearance de- Copyright © 2011 SciRes. JCT 24 Epirubicin-[Anti-HER2/neu] Synthesized with an Epirubicin-(C13 -imino)-EMCS Analog: Anti-Neoplastic Activity Against Chemotherapeutic-Resistant SKBr-3 Mammary Carcinoma in Combination with Organic Selenium veloped followed by incubation at
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