Dual potency anti-HER2/neu and anti-EGFR anthracycline immunoconjugates in chemotherapeutic-resistant mammary carcinoma combined with cyclosporin A and verapamil P-glycoprotein inhibition.
Immunoconjugates of epirubicin were synthesized with monoclonal antibodies against the epidermal growth factor receptors, HER2/neu and EGFR, by creating a sulfhydryl-reactive epirubicin intermediate applying heterobifunctional succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), which was introduced at alpha-monoamide groups of the epirubicin carbohydrate moiety. In parallel, N-succinimidyl-S-acetylthioacetate (SATA) was used to incorporate a sulfhydryl group into immunoglobulin at the terminal amine position of -lysine amino acid residues. Eprirubicin-SMCC-SATA-IgG immunoconjugates were produced by reacting epirubicin-SMCC and SATA-IgG at appropriate molar ratios. Epirubicin-(anti-HER2/neu) and epirubicin-(anti-EGFR) had greater potency against chemotherapeutic-resistant SKBr-3 mammary carcinoma than did epirubicin at epirubicin-equivalent concentrations. Epirubicin-(anti-HER2/neu) was more potent than epirubicin-(anti-EGFR), and a synergistic level of antineoplastic activity was detected with an epirubicin immunoconjugate 50/50 combination. Competitive P-glycoprotein inhibition with cyclosporin A or verapamil enhanced the potency of the epirubicin immunoconjugate 50/50 combination. Minor levels of antineoplastic activity were detected only with an immunoglobulin 50/50 combination of anti-HER2/neu and anti-EGFR. The investigations represent a potential strategy for enhancing the selective internalization, intracellular deposition, and antineoplastic potency of chemotherapeutics in multidrug-resistant neoplasias.
Coyne
C P
CP
Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762, USA. coyne@cvm.msstate.edu
Ross
Matt K
MK
Bailey
John G
JG
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000276:immunology; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015251:Epirubicin / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology; D007074:Immunoglobulin G / Q000737:chemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D016572:Cyclosporine; D015251:Epirubicin; D066246:ErbB Receptors; D018796:Immunoconjugates; D007074:Immunoglobulin G; D018719:Erb-b2 Receptor Tyrosine Kinases; D014700:Verapamil