Synthesis of Gemcitabine-(C<sub>4</sub>-<i>amide</i>)-[anti-HER2/<i>neu</i>] Utilizing a UV-Photoactivated Gemcitabine Intermediate: Cytotoxic Anti-Neoplastic Activity against Chemotherapeutic-Resistant Mammary Adenocarcinoma SKBr-3 — Oak Academic Publishing
Research ArticleOpen AccessGoogle Scholar indexed
Synthesis of Gemcitabine-(C<sub>4</sub>-<i>amide</i>)-[anti-HER2/<i>neu</i>] Utilizing a UV-Photoactivated Gemcitabine Intermediate: Cytotoxic Anti-Neoplastic Activity against Chemotherapeutic-Resistant Mammary Adenocarcinoma SKBr-3
Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Oktibbeha County, USA
,
Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Oktibbeha County, USA
,
Wise Center, Mississippi State University, Oktibbeha County, USA
1 Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Oktibbeha County, USA
2 Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Oktibbeha County, USA
3 Wise Center, Mississippi State University, Oktibbeha County, USA
Gemcitabine is a pyrimidine nucleoside analog that becomes triphosphorylated intracellularly where it competitively inhibits cytidine incorporation into DNA strands. Another mechanism-of-action of gemcitabine (diphosphorylated form) involves irreversible inhibition of the enzyme ribonucleotide reductase thereby preventing deoxyribonucleotide synthesis. Functioning as a potent chemotherapeutic gemcitabine promote decreases in neoplastic cell proliferation and apoptosis which is frequently found to be effective for the treatment of several leukemias and a wide spectrum of carcinomas. A brief plasma half-life in part due to rapid deamination and chemotherapeutic-resistance restricts the utility of gemcitabine in clinical oncology. Selective “targeted” delivery of gemcitabine represents a potential molecular strategy for simultaneously prolonging its plasma half-life and minimizing innocient tissues and organ systems exposure to chemotherapy. The molecular design and an organic chemistry based synthesis reaction is described that initially generates a UV-photoactivated gemcitabine intermediate. In a subsequent phase of the synthesis method the UV-photoactivated gemcitabine intermediate is covalently bonded to a monoclonal immunoglobulin yielding an end-product in the form of gemcitabine-(C 4 - amide )-[anti-HER2/ neu ]. Analysis by SDS-PAGE/chemiluminescent auto-radiography did not detect evidence of gemcitabine-(C 4 - amide )-[anti-HER2/ neu ] polymerization or degradative fragmentation while cell-ELISA demonstrated retained binding-avidity for HER2/ neu trophic membrane receptor complexes highly over-expressed by chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3). Compared to chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3), the covalent immunochemotherapeutic, gemcitabine-(C 4 - amide )-[anti-HER2/ neu ] is anticipated to exert greater levels of cytotoxic anti-neoplastic potency against other neoplastic cell types like pancreatic carcinoma, small-cell lung carcinoma, neuroblastoma, glioblastoma, oral squamous cell carcinoma, cervical epitheliod carcinoma, or leukemia/lymphoid neoplastic cell types based on their reported sensitivity to gemcitabine and gemcitabine covalent conjugates.
T. Kaneko, D. Willner, J. O. Knipe, G. R. Braslawsky, R. S. Greenfield and D. M. Vyas, “New Hydrazone Derivatives of Adriamycin and their Immunoconjugates: A Correlation between Acid-Stability and Cytotoxicity,” Bioconjugate Chemistry, Vol. 2, No. 3, 1991, pp. 133-141. doi:10.1021/bc00009a001
G. Di Stefano, M. Lanza, F. Kratz, L. Merina and L. Fiume, “A Novel Method for Coupling Doxorubicin to Lactosaminated Human Albumin by an Acid Sensitive Hydrazone Bond: Synthesis, Characterization. And Preliminary Biological Properties of the Conjugate,” European Journal of Pharmaceutical Sciences, Vol. 23, No. 4-6, 2004, pp. 393-397. doi:10.1016/j.ejps.2004.09.005
F. Kratz, A. Warnecke, K. Scheuermann, C. Stockmar, J. Schwab, P. Lazar, P. Druckes, C. Hinderling, G. Folkers, I. Fichtner and C. Unger, “Probing the Cysteine-34 Position of Endogenous Serum Albumin with Thiol-Binding, Doxorubicin Derivatives. Improved Efficacy of an Acid-Sensitive Doxorubicin Derivative with Specific Albumin-Binding Properties Compared to That of the Parent Compound,” Journal of Medicinal Chemistry, Vol. 45, No. 25, 2002, pp. 5523-5533. doi:10.1021/jm020276c
C. Unger, B. Haring, M. Medinger, J. Drevs, S. Steinbild, F. Kratz and K. Mross, “Phase I and Pharmacokinetic Study of the (6-Maleimidocaproyl) Hydrazone Derivative of Doxorubicin,” Clinical Cancer Research, Vol. 13, No. 16, 2007, pp. 4858-4866. doi:10.1158/1078-0432.CCR-06-2776
C. Mazuel, J. Grove, G. Gerin and K. P. Keenan, “HPLC-MS/MS Determination of a Peptide Conjugate Prodrug of Doxorubicin, and Its Active Metabolites, Leucine-Doxorubicin and Doxorubicin, in Dog and Rat Plasma,” Journal of Pharmaceutical and Biomedical Analysis, Vol. 33, No. 5, 2003, pp. 1093-1102. doi:10.1016/S0731-7085(03)00434-5
R. S. Greenfield, T. Kaneko, A. Daues, M. A. Edson, K. A. Fitzgerald, L. J. Olech, J. A. Grattan, G. L. Spitalny and G. R. Braslawsky, “Evaluation In-Vitro of Adriamycin Immunoconjugates Synthesized Using an Acid-Sensitive Hydrazone Linker,” Cancer Research, Vol. 50, No. 20, 1990, pp. 6600-6607.
C. P. Coyne, M. Ross, J. Bailey and T. Jones, “Dual Potency Anti-HER2/neu and Anti-EGFR Anthracycline-Immunoconjugates in Chemotherapeutic-Resistant Mammary Carcinoma Combined with Cyclosporin-A and Verapamil P-Glycoprotein Inhibition,” Journal of Drug Targeting, Vol. 17, No. 6, 2009, pp. 474-489. doi:10.1080/10611860903012802
A. Lau, G. Berube, C. H. J. Ford and M. Gallant, “Novel Doxorubicin-Monoclonal Anti-Carcinoembryonic Antigen Antibody Immunoconjugate Activity In-Vivo” Bioorganic and Medicinal Chemistry, Vol. 3, No. 10, 1995, pp. 1305-1312. doi:10.1016/0968-0896(95)00126-2
sub>
4<
/sub>
-<
i>
amide<
/i>
) Intermediate
Organic Chemistry Reaction
Gemcitabine-(C<
sub>
4<
/sub>
-<
i>
amide<
/i>
)-[anti-HER2/<
i>
neu<
/i>
]
Covalent Bond Synthesis
Gemcitabine (C<
sub>
5<
/sub>
-<
i>
methylcarbamate<
/i>
)-[anti-HER2/<
i>
neu<
/i>
]
Cytotoxic Anti-Neoplastic Potency
Chemotherapeutic-Resistant
Mammary Adenocarcinoma
Cell-ELISA
SDS-PAGE
Immunodetection
Chemiluminescent Autoradiography
M. Kruger, U. Beyer, P. Schumacher, C. Unger, H. Zahn and F. Kratz, “Synthesis and Stability of Four Maleimide Derivatives of the Anti-Cancer Drug Doxorubicin for the Preparation of Chemoimmunoconjugates,” Chemical & Pharmaceutical Bulletin, Vol. 45, No. 2, 1997 pp. 399-401. doi:10.1248/cpb.45.399
D. Y. Furgeson, M. R. Dreher and A. Chilkoti, “Structural optimization of a ‘Smart’ Doxorubicin-Polypeptide Conjugate for thermally Targeted Delivery to Solid Tumors,” Journal of Controlled Release, Vol. 110, No. 2, 2006, pp. 362-369. doi:10.1016/j.jconrel.2005.10.006
J. F. Liang and V. C. Yang, “Synthesis of Doxorubicin-Peptide Conjugate with Multidrug Resistant Tumor Cell Killing Activity,” Bioorganic and Medicinal Chemistry Letters, Vol. 15, No. 22, 2005, pp. 5071-5075. doi:10.1016/j.bmcl.2005.07.087
M. Sirova, J. Strohalm, V. Subr, D. Plocova, P. Rossmann, T. Mrkvan, K. Ulbrich and B. Rihova, “Treatment with HPMA Copolymer-Based Doxorubicin Conjugate Containing Human Immunoglobulin Induces Long-Lasting Systemic Anti-Tumor Immunity in Mice,” Cancer Immunol Immunother, Vol. 56, No. 1, 2007, pp. 35-47. doi:10.1007/s00262-006-0168-0
B. K. Wong, D. Defeo-Jones, R. E. Jones, V. M. Garsky, D. M. Feng, A. Oliff, M. Chiba, J. D. Ellis and J. H. Lin, “PSA-Specific and Non-PSA-Specific Conversion of a PSA-Targeted Peptide Conjugate of Doxorubicin to Its Active Metabolite,” Drug Metabolism and Disposition, Vol. 29, No. 3, 2001, pp. 313-318.
G. L. Bidwell, A. N. Davis, I. Fokt, W. Priebe and D. Raucher, “A thermally Targeted Elastin-Like Polypeptide-Doxorubicin Conjugate Overcomes Drug Resistance,” Investigational New Drugs, Vol. 25, No. 4, 2007, pp. 313-326. doi:10.1007/s10637-007-9053-8
K. A. Ajaj, R. Graeser, I. Fichtner and F. Kratz, “In-Vitro and In-Vivo Study of an Albumin-Binding Prodrug of Doxorubicin That Is Cleaved by Cathepsin B,” Cancer Chemotherapy and Pharmacology, Vol. 64, No. 2, 2009, pp. 413-418. doi:10.1007/s00280-009-0942-8
C. Ryppa, H. Mann-Steinberg, I. Fichtner, H. Weber, R. Satchi-Fainaro, M. L. Biniossek and F. Kratz, “In-Vitro and In-Vivo Evaluation of Doxorubicin Conjugates with the Divalent Peptide E-[c(RGDfK)2] That Targets Integrin aVb3,” Bioconjugate Chemistry, Vol. 19, No. 7, 2008 pp. 1414-1422. doi:10.1021/bc800117r
Y. F. Huang, D. Shangguan, H. Liu, J. A. Phillips, X. Zhang, Y. Chen and W. Tan, “Molecular assembly of an Aptamer-Drug Conjugate for Targeted Drug Delivery to Tumor Cells,” A European Journal of Chemical Biology, Vol. 10, No. 5, 2009, pp. 862-868. doi:10.1002/cbic.200800805
Y. Ren, D. Wei and X. Zhan, “Inhibition of P-Glycoprotein and Increasing of Drug-Sensitivity of a Human Carcinoma Cell Line (KB-A-1) by an Anti-Sense Oligodeoxynucleotide-Doxorubicin Conjugate In-Vitro,” Biotechnology and Applied Biochemistry, Vol. 41, No. 2, 2005, pp. 137-143. doi:10.1042/BA20040058
Y. Ren, X. Zhan, D. Wei and J. Liu, “In-Vitro Reversal MDR of Human Carcinoma Cell Line by an Antisense Oligodeoxynucleotide-Doxorubicin Conjugate,” Biomedicine & Pharmacotherapy, Vol. 58. No. 9, 2004, pp. 520-526.
L. Kovar, T. Etrych, M. Kabesova, V. Subr, D. Vetvicka, O. Hovorka, J. Strohalm, J. Sklenar, P. Chytil, K. Ulbrich and B. Rihova, “Doxorubicin Attached to HPMA Copolymer via Amide Bond Modifies the Glycosylation Pattern of EL4 Cells,” Tumor Biology, Vol. 31. No. 4, 2010, pp. 233-242. doi:10.1007/s13277-010-0019-7
T. Lammers, V. Subr, K. Ulbrich, P. Peschke, P. E. Huber, W. E. Hennink and G. Storm, “Simultaneous Delivery of Doxorubicin and Gemcitabine to Tumors in Vivo Using Prototypic Polymeric Drug Carriers,” Biomaterials, Vol. 30, No. 20, 2009, pp. 3466-3475. doi:10.1016/j.biomaterials.2009.02.040
H. Krakovicova, T. Ethch and K. Ulbrich, “HPMA-Based Polymerconjugates with Drug Combinations,” European Journal of Pharmacology, Vol. 37. No. 3-4, 2009, pp. 4050-4412.
N. Cao and S. S. Feng, “Doxorubicin Conjugated to D-alpha-Tocopheryl Polyethylene Glycol 1000 Succinate (TPGS): Conjugation Chemistry, Characterization, In-Vitro and In-Vivo Evaluation,” Biomaterials, Vol. 29, No. 28, 2008, pp. 3856-3865. doi:10.1016/j.biomaterials.2008.05.016
P. C. Rodrigues, U. Beyer, P. Schumacher, T. Roth, H. H. Fiebig, C. Unger, L. Messori, P. Orioli, D. H. Paper, R. Mulhaupt and F. Kratz, “Acid-Sensitive Polyethylene Glycol Conjugates of Doxorubicin: Preparation, In-Vitro Efficacy and Intracellular Distribution,” Bioorganic & Medicinal Chemistry, Vol. 7, No. 11, 1999, pp. 2517-2524. doi:10.1016/S0968-0896(99)00209-6
F. Kratz, “Albumin as a Drug Carrier: Design of Prodrugs, Drug Conjugates and Nanoparticles,” Journal of Con- trolled Release, Vol. 132, No. 3, 2008, pp. 171-183. doi:10.1016/j.jconrel.2008.05.010
K. Inoh, H. Muramatsu, S. Torii, S. Ikematsu, M. Oda, H. Kumai, S. Sakuma, T. Inui, T. Kimura and T. Muramatsu, “Doxorubicin-conjugated Anti-Midkine Monoclonal Antibody as a Potential Anti-Tumor Drug,” Japanese Journal of Clinical Oncology, Vol. 36, No. 4, 2006, pp. 207-211. doi:10.1093/jjco/hyl004
G. L. Griffiths, M. J. Mattes, R. Stein, S. V. Govindan, I. D. Horak, H. J. Hansen and D. M. Goldenberg, “Cure of SCID Mice Bearing Human B-Lymphoma Xenografts by an Anti-CD74 Antibody-Anthracycline Drug Conjugate,” Clinical Cancer Research, Vol. 9, No. 17, 2003, pp. 6567-6571.
P. Sapra, R. Stein, J. Pickett, Z. Qu, S. Govindan, V, T. M. Cardillo, H. J. Hanson, I. D. Horak, G. L. Griffiths and D. M. Goldenberg, “Anti-CD74 Antibody-Doxorubicin Conjugate, IMMU-110, in a Human Multiple Myeloma Xenograph and in Monkeys,” Clinical Cancer Research, Vol. 11, No. 14, 2005, pp. 5257-5264. doi:10.1158/1078-0432.CCR-05-0204
H. M. Yang and R. A. Reisfeld, “Doxorubicin Conjugated with Monoclonal Antibody Directed to a Human Melanoma-Associated Proteoglycan Suppresses Growth of Established Tumor Xenografts in Nude Mice,” Proceedings of the National Academy of Sciences, Vol. 85, 1988, pp. 1189-1193. doi:10.1073/pnas.85.4.1189
P. A. Trail, D. Willner, S. J. Lasch, A. J. Henderson, S. Hofstead, A. M. Casazza, R. A. Firestone, I. Hellstrom and K. E. Hellstrom, “Cure of Xenografted Human Carcinomas by BR96-Doxorubicin Immunoconjugates,” Science, Vol. 261, No. 5118, 1993, pp. 212-215. doi:10.1126/science.8327892
E. Diener, U. Diner, A. Sinha, S. Xie and R. Vergidis, “Specific Immunosuppression by Immunotoxins Containing Daunomycin,” Science, Vol. 231, No. 4734, 1986, pp. 148-150. doi:10.1126/science.3484557
R. O. Dillman, D. E. Johnson, J. Ogden and D. Beidler, “Significance of Antigen, Drug, and Tumor Cell Targets in the Preclinical Evaluation of Doxorubicin, Daunorubicin, Methotrexate, and Mitomycin-C Monoclonal Anti-body Immunoconjugates,” Molecular Biotherapy, Vol. 1, 5, 1989, pp. 250-255.
M. Page, D. Thibeault, C. Noel and L. Dumas, “Coupling a Preactivated Daunorubicin Derivative to Antibody. A New Approach,” Anticancer Research, Vol. 10, No. 2A, 1990, pp. 353-357.
J. Reményi, B. Balázs, S. Tóth, A. Falus, G. Tóth and F. Hudecz, “Isomer-Dependent Daunomycin Release and in Vitro Antitumour Effect of Cis-Aconityl-Daunomycin,” Biochemical and Biophysical Research Communications, Vol. 303, No. 2, 2003, pp. 556-561. doi:10.1016/S0006-291X(03)00394-2
J. R. Ogden, K. Leung, S. A. Kunda, M. W. Telander, B. P. Avner, S. K. Liao, G. B. Thurman and R. K. Oldham, “Immunoconjugates of Doxorubicin and Murine Antihuman Breast Carcinoma Monoclonal Antibodies Prepared Via an N-Hydroxysuccinimide Active Ester Intermediate of Cis-Aconityl-Doxorubicin: Preparation and in Vitro Cytotoxicity,” Molecular Biotherapy, Vol. 1, No. 3, 1989, pp. 170-174.
C. P. Coyne, T. Jones and T. Pharr, “Synthesis of a Covalent Gemcitabine-(Carbamate)-[Anti-HER2/neu] immunochemotherapeutic and Cytotoxic Anti-Neoplastic Activity against Chemotherapeutic-Resistant SKBr-3 Mammary Carcinoma,” Bioorganic and Medicinal Chemistry, Vol. 19, No. 1, 2011, pp. 67-76. doi:10.1016/j.bmc.2010.11.046
A. I. Shamseddine, M. J. Khalifeh, F. H. Mourad, A. A. Chehal, A. Al-Kutoubi, J. Abbas, M. Z. Habbal, L. A. Malaeb and A. B. Bikhazi, “Comparative Pharmacokinetics and Metabolic Pathway of Gemcitabine During Intravenous and Intra-Arterial Delivery in Unresectable Pancreatic Cancer Patients,” Clinical Pharmacokinetics, Vol. 44, No. 9, 2005, pp. 957-967. doi:10.2165/00003088-200544090-00005
E. Giovannetti, A. C. Laan, E. Vasile, C. Tibaldi, S. Nannizzi, S Ricciardi, A. Falcone, R. Danesi and G. J. Peters, “Correlation between Cytidine Deaminase Genotype and Gemcitabine Deamination in Blood Samples,” Nucleosides Nucleotides Nucleic Acids, Vol. 27, No. 6, 2008, pp. 720-725. doi:10.1080/15257770802145447
J. A. Gilbert, O. E. Salavaggione, Y. Ji, L. L. Pelleymounter, B. W. Eckloff, E. D. Wieben, M. M. Ames and R. M. Weinshilboum, “Gemcitabine Pharmacogenomics: Cytidine Deaminase and Deoxycytidylate Deaminase Gene Resequencing and Functional Genomics,” Clinical Cancer Research, Vol. 12, No. 6, 2006, pp. 1794-1803. doi:10.1158/1078-0432.CCR-05-1969
R. L. Alexander, B. T. Greene, S. Torti and V. G. L. Kucera, “A Novel Phospholipid Gemcitabine Conjugate Is Able to Bypass Three Drug-Resistance Mechanisms,” Cancer Chemotherapy and Pharmacology, Vol. 56, No. 1, 2005, pp. 15-21. doi:10.1007/s00280-004-0949-0
R. J. Pietras, M. D. Pegram, R. S. Finn, D. A. Maneval and D. J. Slamon, “Remission of Human Breast Cancer Xenografts on therapy with Humanized Monoclonal Antibody to HER-2 Receptor and DNA-Reactive Drugs,” Oncogene, Vol. 17, No. 17, 1998, pp. 2235-2249. doi:10.1038/sj.onc.1202132
R. Marches and J. W. Uhr, “Enhan Cement of the p27Kip1-Mediated Antiproliferative Effect of Trastuzumab (Herceptin) on HER2-Overexpressing Tumor Cells,” International Journal of Cancer, Vol. 112, No. 3, 2004, pp. 492-501. doi:10.1002/ijc.20378
M. Sliwkowski, X, J. A. Lofgren, G. D. Lewis, T. E. Hotaling, B. M. Fendly and J. A. Fox, “Nonclinical Studies Addressing the Mechanism of Action of Trastuzumab (Herceptin),” Seminars in Oncology, Vol. 26, Suppl. 12, 1999, pp. 60-70.
N. U. Lin, L. A. Carey, M. C. Liu, J. Younger, S. E. Come, M. Ewend, G. Harris, E. Bullitt, A. D. Van den Abbeele, J. W. Henson, X. Li, R. Gelman, H. J. Burstein, E. Kasparian, D. G. Kirsch, A. Crawford, F. Hochberg and E. P. Winer, “Phase II Trial of Lapatinib for Brain Metastases in Patients with Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer,” Journal of Clinical Oncology, Vol. 26, No. 12, 2008, pp. 1993-1999. doi:10.1200/JCO.2007.12.3588
M. A. Cobleigh, C. L. Vogel, D. Tripathy, N. J. Robert, S. Scholl, L. Fehrenbacher, J. Wolter, V. Paton, S. Shak, G. Lieberman and D. J. Slamon, “Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing Metastatic Breast Cancer That Has Progressed after Chemotherapy for Metastatic Disease,” Journal of Clinical Oncology, Vol. 17, No. 9, 1999, pp. 2639-2648.
C. L. Vogel, M. A. Cobleigh, D. Tripathy, J. C. Gutheil, L. N. Harris, L. Fehrenbacher, D. J. Slamon, M. Murphy, W. F. Novotny, M. Burchmore, S. Shak, S. J. Stewart and M. Press, “Efficacy and Safety of Trastuzumab as a Single Agent in First-Line Treatment of HER2-Overexpressing Metastatic Breast Cancer,” Journal of Clinical Oncology, Vol. 20, No. 3, 2002, pp. 719-726. doi:10.1200/JCO.20.3.719
G. D. Lewis Phillips, G. Li, D. L. Dugger, L. M. Crocker, K. L. Parsons, E. Mai, W. A. Blattler, J. M. Lambert, R. Chari, V, R. J. Lutz, W. L. Wong, F. S. Jacobson, H. Koeppen, R. H. Schwall, S. R. Kenkare-Mitra, S. D. Spencer and M. X. Sliwkowski, “Targeting HER2-Positive Breast Cancer with Trastuzumab-DM1, an Antibody-Cytotoxic Drug Conjugate,” Cancer Research, Vol. 68, No. 22, 2008, pp. 9280-9290. doi:10.1158/0008-5472.CAN-08-1776
J. A. García-Sáenz, M. Martín, A. Calles, C. Bueno, L. Rodríguez, J. Bobokova, A. Custodio, A. Casado and E. Díaz-Rubio, “Bevacizumab in Combination with Metronomic Chemotherapy in Patients with Anthracycline- and Taxane-Refractory Breast Cancer,” Journal of Chemotherapy, Vol. 20, No. 5, 2008, pp. 632-639.
D. J. Slamon, B. Leyland-Jone, S. Shak, H. Fuchs, V. Paton, A. Bajamonde, T. Fleming, W. Eiermann, J. Wolter and M. Pegram, “Use of Chemotherapy plus Monoclonal Antibody against HER2 for Metastatic Breast Cancer That Overexpress HER2,” The New Eng- land Journal of Medicine, Vol. 344, No. 11, 2001, pp. 786-792. doi:10.1056/NEJM200103153441101
U. Beyer, T. Roth, P. Schumacher, G. Maier, A. Unold, A. W. Frahm, H. H. Fiebig, C. Unger and F. Kratz, “Synthesis and In-Vitro Efficacy of Transferring Conjugates of the Anticancer Drug Chlorambucil,” Journal of Medicinal Chemistry, Vol. 41, No. 15, 1998, pp. 2701-2708. doi:10.1021/jm9704661
L. C. Xu, M. Nakayama, K. Harada, A. Kuniyasu, H. Nakayama, S. Tomiguchi, A. Kojima, M. Takahashi, M. Ono, Y. Arano, H. Saji, Z. Yao, H. Sakahara, J. Konishi and Y. Imagawa, “Bis(Hydroxamamide)-Based Bifunctional Chelating Agent for 99mTc Labeling of Polypeptides,” Bioconjugate Chemistry, Vol. 10, No. 1, 1999, pp. 9-17. doi:10.1021/bc980024j
Y. Arano, T. Uezono, H. Akizawa, M. Ono, K. Wakisaka, M. Nakayama, H. Sakahara, J. Konishi and A. Yokoyama, “Reassessment of Diethylenetriaminepentaacetic Acid (DTPA) as a Chelating Agent for Indium-111 Labeling of Polypeptides Using a Newly Synthesized Monoreactive DTPA Derivative,” Journal of Medicinal Chemistry, Vol. 39 No. 18, 1996, pp. 3451-3460. doi:10.1021/jm950949+
M. E. Annunziato, U. S. Patel, M. Ranade and P. S. Palumbo, “p-Maleimidophenyl Isocyanate: A Novel Heterbifunctional Linker for Hydroxyl to Thiol Coupling,” Bioconjugate Chemistry, Vol. 4, No. 3, 1993, pp. 212-218. doi:10.1021/bc00021a005
Q. Liu, J. R. de Wijn and C. A. van Blitterswijk, “Covalent Bonding of PMMA, PBMA, and Poly(HEMA) to Hydroxyapatite Particles,” Journal of Biomedical Materials Research, Vol. 40, No. 2, 1998, pp. 257-263. doi:10.1002/(SICI)1097-4636(199805)40:2 3.0.CO;2-J
X. L. Wang, Y. Huang, J. Zhu, Y. B. Pan, R. He and Y. Z. Wang, “Chitosan-Graft Poly(p-Dioxanone) Copolymers: Preparation, Characterization, and Properties,” Carbohydrate Research, Vol. 344, No. 6, 2009, pp, 801-807.
S. M. Ali, A. R. Khan, M. U. Ahmad, P. Chen, S. Sheikh and I. Ahmad, “Synthesis and Biological Evaluation of Gemcitabine-Lipid Conjugate (NEO6002),” Bioorganic & Medicinal Chemistry Letters, Vol. 15, No. 10, 2005, pp. 2571-2574. doi:10.1016/j.bmcl.2005.03.046
P. Chen, P. Y. Chien, A. R. Khan, S. Sheikh, S. M. Ali, M. U. Ahmad and I. Ahmad, “In-Vitro and in-Vivo Anti-Cancer Activity of a Novel Gemcitabine-Cardiolipin Conjugate,” Anticancer Drugs, Vol. 17, No. 1, 2006, pp. 53-61. doi:10.1097/01.cad.0000185182.80227.48
L. V. Kiew, S. K. Cheong, K. Sidik and L. Y. Chung, “Improved Plasma Stability and Sustained Release Profile of Gemcitabine Via Polypeptide Conjugation,” International Journal of Pharmaceutics, Vol. 391, No. 1-2, 2010, pp. 212-220. doi:10.1016/j.ijpharm.2010.03.010
P. Guo, J. Ma, S. Li, Z. Guo, A. L. Adams and J. M. Gallo, “Targeted Delivery of a Peripheral Benzodiazepine Receptor Ligand-Gemcitabine Conjugate to Brain Tumors in a Xenograft Model,” Cancer Chemotherapy and Pharmacology, Vol. 48, No. 2 , 2001, pp. 169-176. doi:10.1007/s002800100284
R. L. Alexander, S. L. Morris-Natschke, K. S. Ishaq, R. A. Fleming and G. L. Kucera, “Synthesis of Cytotoxic Activity of Two Novel 1-Dodecylthio-2-Decyloxypropyl-3-Phophatidic Acid Conjugates with Gemcitabine and Cytosine Arabinoside,” Journal of Medicinal Chemistry, Vol. 46, 19, 2003, pp. 4205-4208. doi:10.1021/jm020571x
Z. Guo and J. M. Gallo, “Selective Protection of 2’,2’- Difluorodexoycytidine (Gemcitabine),” The Journal of Organic Chemistry, Vol. 64, No. 22, 1999, pp. 8319-8322. doi:10.1021/jo9911140
P. A. Trail, D. Willner, J. Knipe, A. J. Henderson, S. J. Lasch, M. E. Zoeckler, M. D. TrailSmith, T. W. Doyle, H. D. King, A. M. Casazza, J. Brown, S. J. Hofstead, R. S. Greenfield, R. A. Firestone, K. Mosure, K. F. Kadow, M. B. Yang, K. E. Hellstrom and I. Hellstrom, “Effect of linker Variation on the Stability, Potency and Efficacy of Carcinoma-Reactive BR64-Doxorubicin Immunoconjugates,” Cancer Research, Vol. 57, No. 1, 1997, pp. 100-105.
T. Etrych, T. Mrkvan, B. Ríhová and K. Ulbrich, “Star-Shaped Immunoglobulin-Containing HPMA-Based Conjugates with Doxorubicin for Cancer Therapy,” Journal of Controlled Release, Vol. 122, No. 1, 2007, pp. 31-38. doi:10.1016/j.jconrel.2007.06.007
J. Liu, H. Zhao, K. J. Volk, S. E. Klohr, E. H. Kerns and M. S. Lee, “Analysis of Monoclonal Antibody and Immunoconjugate Digests by Capillary Electrophoresis and Capillary Liquid Chromatography,” Journal of Chromatography A, Vol. 735, No. 1-2, 1996, pp. 357-366. doi:10.1016/0021-9673(95)01054-8
F. Kratz, G. Ehling, H.-M. Kauffmann and C. Unger, “Acute and Repeat-Dose Toxicity Studies of the (6-Maleimidocaproyl)Hydrazone Derivative of Doxorubicin (DOXO-EMCH), an Albumin-Binding Prodrug of the Anticancer Agent Doxorubicin,” Human & Experimental Toxicology, No. 26, No. 1, 2007, pp. 19-35. doi:10.1177/0960327107073825
D. Lebrecht, A. Geist, U. P. Ketelsen, J. Haberstroh, B. Setzer, F. Kratz and U. Walker, “The 6-Maleimidocaproyl Hydrazone Derivative of Doxorubicin (Doxoemch) Is Superior to Free Doxorubicin with Respect to Cardiotoxicity and Mitochondrial Damage,” International Journal of Cancer, Vol. 120, No. 4, 2006, pp. 927-934.
F. Kratz, U. Beyer, P. Collery, F. Lechenault, A. Cazabat, P. Schumacher, U. Falken and C. Unger, “Preparation, Characterization and In-Vitro Efficacy of Albumin Conjugates of Doxorubicin,” Biological and Pharmaceutical Bulletin, Vol. 21, No. 1, 1998, pp. 56-61. doi:10.1248/bpb.21.56
F. Kratz, U. Beyer, T. Roth, N. Tarasova, P. Collery, F. Lechenault, A. Cazabat, P. Schumacher, C. Unger and U. Falken, “Transferrrin Conjugates of Doxorubicin: Synthesis, Characterization, Cellular Uptake, and In-Vitro Efficacy,” Journal of Pharmaceutical Sciences, Vol. 87, No. 3, 1998, pp. 338-346. doi:10.1021/js970246a
M. N. Kirstein, I. Hassan, D. E. Guire, D. R. Weller, J. W. Dagit, J. E. Fisher and R. P. Remmel, “High-Performance Liquid Chromatographic Method for the Determination of Gemcitabine and 2’,2’-Difluorodeoxyuridine in Plasma and Tissue Culture Media,” Journal of Chromatography B: Biomedical Sciences and Applications, Vol. 835, No. 1-2 , 2006, pp. 136-142. doi:10.1016/j.jchromb.2006.03.023
V. Reichelova, F. Albertioni and J. Liliemark, “Determination of 2-Chloro-2’-Deoxyadenosine Nucleotides in Leukemic Cells by Ion-Pair High-Performance Liquid Chromatography,” Journal of Chromatography B: Biomedical Sciences and Applications, Vol. 682, No. 1, 1996, pp. 115-123. doi:10.1016/0378-4347(96)00048-5
C. P. Coyne, T. Jones, A. Sygula, J. Bailey and L. Pinchuk, “Epirubicin-[Anti-HER2/neu] Synthesized with an Epirubicin-(C13-Imino)-EMCS Analog: Anti-Neo-plastic Activity Against Chemotherapeutic-Resistant SKBr-3 Mammary Carcinoma in Combination with Organic Selenium,” Journal of Cancer Therapy, Vol. 2, No. 1, 2011, pp. 22-39. doi:10.4236/jct.2011.21004
C. P. Coyne, T. Jones and R. Bear, “Synthesis of Epirubicin-(C3-amide)-[Anti-HER2/neu] utilizing a UV-Photoactivated Epirubicin Intermediate,” Cancer Biotherapy and Radiopharmaceuticals, Vol. 27, No. 1, 2012, pp. 41-55. doi:10.1089/cbr.2011.1097
U. Beyer, B. Rothen-Rutishauser, C. Unger, H. Wunderli-Allenspach and F. Kratz, “Difference in the Intracellular Distribution of Acid-Sensitive Doxorubicin-Protein Conjugates in Comparison to Free and Liposomal-Formulated Doxorubicin as Shown by Confocal Microscopy,” Pharmaceutical Research, Vol. 18, No. 1, 2001, pp. 29-38. doi:10.1023/A:1011018525121
J. A. Sinkule, S. T. Rosen and J. A. Radosevich, “Monoclonal Antibody 44-3A6 Doxorubicin Immunoconjugates: Comparative in Vitro Anti-Tumor Efficacy of Different Conjugation Methods,” Tumour Biology, Vol. 12, No. 4, 1991, pp 198-206. doi:10.1159/000217705
G. P. Sivam, P. J. Martin, R. A. Reisfeld and B. M. Mueller, “Therapeutic Efficacy of a Doxorubicin Immunoconjugate in a Preclinical Model of Spontaneous Metastatic Human Melanoma,” Cancer Research, Vol. 55, No. 11, 1995, pp. 2352-2356.
R. L. Alexander and G. L. Kucera, “Lipid nucleoside Conjugates for the Treatment of Cancer,” Current Pharmaceutical Design, Vol. 11, No. 9, 2005, pp. 1079-1089. doi:10.2174/1381612053507602
P. Lagisetty, P. Vilekar, V. Awasthi, “Synthesis of Radiolabeled Cytarabine Conjugates,” Bioorganic & Medicinal Chemistry Letters, Vol. 19, No. 16, 2009, pp. 4764-4767. doi:10.1016/j.bmcl.2009.06.056
F. Castelli, M. G. Sarpietro, M. Ceruti, F. Rocco and L. Cattel, “Characterization of Lipophilic Gemcitabine Prodrug-Liposomal Membrane Interaction by Differential Scanning Calorimetry,” Molecular Pharmaceutics, Vol. 3, No. 6, 2006, pp. 737-744. doi:10.1021/mp060059y
L. H. Reddy, C. Dubernet, S. L. Mouelhi, P. E. Marque, D. Desmaele and P. Couvreur, “A New Nanomedicine of Gemcitabine Displays Enhanced Anticancer Activity in Sensitive and Resistant Leukemia Types,” Journal of Controlled Release, Vol. 124, No. 1-2, 2007, pp. 20-27. doi:10.1016/j.jconrel.2007.08.018
S. H. Frost, H. Jensen and S. Lindegren, “In-Vitro Evaluation of Avidin Antibody Pretargeting Using [211At]-Labeled and Biotinylated Poly-L-Lysine as Effector Molecule,” Cancer, Vol. 116, No. S4, 2010, pp. 1101-1110. doi:10.1002/cncr.24798
H. Karacay, R. M. Sharkey, S. Govindan, V, W. J. McBride, D. M. Goldenberg, H. J. Hansen and G. L. Griffiths, “Development of a Streptavidin-Anti-Carcinoembryonic Antigen Antibody, Radiolabeled Biotin Pretargeting Method for Radioimmunotherapy of Colorectal Cancer. Reagent Development,” Bioconjugate Chemistry, Vol. 8, No. 4, 1997, pp. 585-594. doi:10.1021/bc970102n
A. Lau, G. Bérubéand C. H. ford, “Conjugation of Doxorubicin to Monoclonal Anti-Carcinoembryonic Antigen Antibody Via Novel Thiol-Directed Cross-Linking Reagents,” Bioorganic & Medicinal Chemistry, Vol. 3, No. 10, 1995, pp. 1299-1304. doi:10.1016/0968-0896(95)00125-Z
A. K. Fry, K. F. Schilke, J. McGuire and K. E. Bird, “Synthesis and Anticoagulant Activity of Heparin Immobilized ‘End-On’ to Polystyrene Microspheres Coated with End-Group Activated Polyethylene Oxide,” Journal of Biomedical Materials Research Part B: Applied Biomaterials, Vol. 94, No. 1, 2010, pp. 187-195.
M. H. Vingerhoeds, H. J. Haisma, S. O. Belliot, R. H. Smit, D. J. Crommelin and G. Storm, “Immunoliposomes as Enzyme-Carriers (Immuno-Enzymosomes) for Anti-body-Directed Enzyme Prodrug Therapy (ADEPT): Optimization of Prodrug Activating Capacity,” Pharmaceutical Research, Vol. 13, No. 4, 1996, pp. 604-610. doi:10.1023/A:1016010524510
K. Fujiwara, M. Yasuno and T. Kitagawa, “Novel Preparation Method of Immunogen for Hydrophobic Hapten, Enzyme Immunoassay for Daunomycin and Adriamycin,” Journal of Immunological Methods, Vol. 45, No. 2, 1981, pp. 195-203. doi:10.1016/0022-1759(81)90213-1
Y. Wang, X. Liu and D. J. Hnatowich, “An improved Synthesis of NHS-MAG3 for Conjugation and Radiolabeling of Biomolecules with [99mTc] at Room Temperature,” Nature Protocols, Vol. 2, No. 4, 2007, pp. 972-978. doi:10.1038/nprot.2007.144
P. Joshi, K. F. Schilke, A. Fry, J. McGuire and K. Bird, “Synthesis and Evaluation of Heparin Immobilized ‘Side-On’ to Polystyrene Microspheres Coated with End-Group Activated Polyethylene Oxide,” International Journal of Biological Macromolecules, Vol. 47, No. 2 , 2010, pp. 98-103. doi:10.1016/j.ijbiomac.2010.05.015
J. Vega, S. Ke, Z. Fan, S. Wallace, C. Charsangavej and C. Li, “Targeting Doxorubicin to Epidermal Growth Factor Receptors by Site-Specific Conjugation of C225 to Poly(L-Glutamic Acid) Through a Polyethylene Glycol Spacer,” Pharmaceutical Research, Vol. 20, No. 5, 2003 pp. 826-832. doi:10.1023/A:1023454107190
R. Jin, L. S. Moreira Teixeira, A. Krouwels, P. J. Dijkstra, C. A. van Blitterswijk, M. Karperien and J. Feijen, “Synthesis and Characterization of Hyaluronic Acid-Poly (Ethylene Glycol) Hydrogels via Michael addition: an Injectable Biomaterial for Cartilage Repair,” Acta Biomater, Vol. 6, No. 6, 2010, pp. 1968-1977. doi:10.1016/j.actbio.2009.12.024
J. Morales-Sanfrutos, A. Megia-Fernandez, F. Hernandez-Mateo, M. D. Giron-Gonzalez MD, R. Salto Gonzalez and F. Santoyo-Gonzalez, “Alkyl Sulfonyl Derivatized PAMAM-G2 Dendrimers as Nonviral Gene Delivery Vectors with Improved Transfection Efficiencies,” Organic & Biomolecular Chemistry, Vol. 9, No. 3, 2011, pp. 851-864. doi:10.1039/c0ob00355g
M. Haas, F. Moolenaar, A. Elsinga, E. A. Van der Wouden, P. E. De Jong, D. K. F. Meijer and D. D. Zeeuw, “Targeting of Doxorubicin to the Urinary Bladder of the Rat Shows Increased Cytotoxicity in the Bladder Urine Combined with an Absence of Renal Toxicity,” Journal of Drug Targeting, Vol. 10, 1, 2002, pp. 81-89. doi:10.1080/10611860290007568
American Cancer Society, “Cancer Facts and Figures 2004,” American Cancer Society, 2004, pp. 1-60.
H. M. Yang and R. A. Reisfeld, “Pharmacokinetics and Mechanism of Action of a Doxorubicin-Monoclonal Antibody 9. 2. 27 Conjugate Directed to a Human Melanoma Proteoglycan,” Journal of the National Cancer Institute, Vol. 80, No. 14, 1988, pp. 1154-1159. doi:10.1093/jnci/80.14.1154
S. Lutsenko, V, N. B. Feldman and S. E. Severin, “Cytotoxic and Antitumor Activities of Doxorubicin Conjugates with the Epidermal Growth Factor and Its Receptor-Binding Fragment,” Journal of Drug Targeting, Vol. 10, No. 7, 2002, pp. 567-571. doi:10.1080/1061186021000038058
C. W. Michalski, M. Erkan, D. Sauliunaite, T. Giese, R. Stratmann, C. Sartori, N. A. Giese, H. Friess and J. Kleeff, “Ex-Vivo Chemosensitivity Testing and Gene Expression Profiling Predict Response Towards Adjuvant Gemcitabine Treatment in Pancreatic Cancer,” British Journal of Cancer, Vol. 99, No. 5, 2008, pp. 760-767. doi:10.1038/sj.bjc.6604528
T. Hoang, K. Kim, A. Jaslowski, P. Koch, P. Beatty, J. McGovern, M. Quisumbing, G. Shapiro, R. Witte and J. H. Schiller, “Phase II Study of Second-Line Gemcitabine in Sensitive Or Refractory Small Cell Lung Cancer,” Lung Cancer, Vol. 42, No. 1, 2003, pp. 97-102. doi:10.1016/S0169-5002(03)00273-3
J. Bierau, A. H. van Gennip, R. Leen, R. Meinsma, H. N. Caron and A. B. van Kuilenburg, “Cyclopentenyl Cytosine-Induced Activation of Deoxycytidine Kinase Increases Gemcitabine Anabolism and Cytotoxicity in Neuroblastoma,” Cancer Chemotherapy and Pharmacology, Vol. 57, No. 1, 2006, pp. 105-113. doi:10.1007/s00280-005-0005-8
V. Santini, G. D'Ippolito, P. A. Bernabei, A. Zoccolante, A. Ermini and P. Rossi-Ferrini, “Effects of Fludarabine and Gemcitabine on Human Acute Myeloid Leukemia Cell Line HL 60: Direct Comparison of Cytotoxicity and Cellular Ara-C Uptake Enhancement,” Leukemia Research, Vol. 20, No. 1, 1996, pp. 37-45. doi:10.1016/0145-2126(95)00106-9
H. Mueller, M. U. Kassack and M. Wiese, “Comparison of the Usefulness of the MTT, ATP and Calcein Assays to Predict the Potency of Cytotoxic Agents in Various Human Cancer Cell Lines,” Biomolecular Screening, Vol. 9, No. 6, 2004, pp. 506-515. doi:10.1177/1087057104265386
E. Ulukaya, F. Ozdikicioglu, A. Y. Oral and M. Dermirci, “The MTT Assay Yields a Relatively Lower Result of Growth Inhibition than the ATP Assay Depending on the Chemotherapeutic Drug Tested,” Toxicol in Vitro, Vol. 22, No. 1, 2008, pp. 232-239. doi:10.1016/j.tiv.2007.08.006
M. Varache-Lembège, S. Larrouture, D. Montaudon, J. Robert and A. Nuhrich, “Synthesis and Antiproliferative Activity of Aryl- and Heteroaryl-Hydrazones Derived from Xanthone Carbaldehydes,” European Journal of Medicinal Chemistry, Vol. 43, No. 6, 2008, pp. 1336-1343. doi:10.1016/j.ejmech.2007.09.003
M. D. Kars, O. D. Iseri, U. Gunduz and J. Molnar, “Reversal of Multidrug Resistance by Synthetic and Natural Compounds in Drug-Resistant MCF-7 Cell Lines,” Chemotherapy, Vol. 54, No. 3, 2008, pp. 194-200. doi:10.1159/000140462
H. Huang, E. Pierstorff, E. Osawa and D. Ho, “Active Nanodiamond Hydrogels for Chemotherapeutic Delivery,” Nano Letters, Vol. 7, No. 11, 2007, pp. 3305-3314. doi:10.1021/nl071521o
M. C. Dery, C. Van Themsche, D. Provencher, A. M. Mes-Masson and E. Asselin, “Characterization of EN-1078D, a poorly differentiated human endometrial carcinoma cell line: a novel tool to study endometrial invasion in-vitro,” Reproductive Biology and Endocrinology, Vol. 5, 2007, pp. 38-39. doi:10.1186/1477-7827-5-38
B. Spee, M. D. Jonkers, B. Arends, G. R. Rutteman, J. Rothuizen and L. C. Penning, “Specific Down-Regulation of XIAP with RNA Interference Enhances the Sensitivity of Canine Tumor Cell-Lines to Trail and Doxorubicin” Molecular Cancer, Vol. 5, 2006, p. 34. doi:10.1186/1476-4598-5-34
N. Denora, V. Laquintana, A. Trapani, A. Lopedota, A. Latrofa, J. M. Gallo and G. Trapani, “Translocator Protein (TSPO) Ligand-Ara-C (cytarabine) Conjugates as a Strategy to Deliver Antineoplastic Drugs and to Enhance Drug Clinical Potential,” Molecular Pharmaceutics, Vol. 7, No. 6, 2010, pp. 2255-2269. doi:10.1021/mp100235w
W. C. Shen and H. J. Ryser, “Cis-Aconityl Spacer between Daunomycin and Macromolecular Carriers: A Model of pH-Sensitive Linkage Releasing Drug from a Lysosomotrophic Conjugates,” Biochemical and Biophysical Research Communications, Vol. 102, No. 3, 1981, pp. 1048-1054. doi:10.1016/0006-291X(81)91644-2
Y. Zhang, N. Wang, N. Li, T. Liu and Z. Dong, “The Antitumor Effect of Adriamycin Conjugated with Monoclonal Antibody against Gastric Cancer In-Vitro and In-Vivo,” Acta Pharmaceutica Sinica, Vol. 27, No. 5, 1992, pp. 325-330.
E. Aboud-Pirak, E. Hurwitz, F. Bellot, J. Schlessinger and M. Sela, “Inhibition of Human Tumor Growth in Nude Mice by a Conjugate of Doxorubicin with Monoclonal Antibodies to Epidermal Growth Factor Receptor,” Proceedings of the National Academy of Sciences, Vol. 86, No. 10, 1989, pp. 3778-3781. doi:10.1073/pnas.86.10.3778
C. P. Coyne, B. W. Fenwick and J. Ainsworth, “Anti-Neoplastic Activity of Chemotherapeutic “Loaded” Neutrophils against Human Mammary Carcinoma,” Biotherapy, Vol. 10, No. 2, 1997, pp. 145-159. doi:10.1007/BF02678542
M. D. Pegram, A. Lopez, G. Konecny and D. J. Slamon, “Trastuzumab and Chemotherapeutics: Drug Interactions and Synergies,” Seminars in Oncology, No. 27, Suppl. 11, 2000, pp. 21-25.
D. Slamon and, M. Pegram, “Rationale for Trastuzumab (Herceptin) in Adjuvant Breast Cancer Trials,” Seminars in Oncology, Vol. 28, Suppl. 3, 2001, pp. 13-19. doi:10.1053/sonc.2001.22812
E. P. Winer and H. J. Burstein, “New Combinations with Herceptin in Metastatic Breast Cancer,” Oncology, Vol. 61, Suppl. 2, 2001, pp. 50-57. doi:10.1159/000055402
S. Kim, C. N. Prichard, M. N. Younes, Y. D. Yazici, S. A. Jasser, B. N. Bekele and J. N. Myers, “Cetuximab and Irinotecan Interact Synergistically to Inhibit the Growth of Orthotopic Anaplastic Thyroid Carcinoma Xenografts in Nude Mice,” Clinical Cancer Research, Vol. 12, No. 2, 2006, pp. 600-607. doi:10.1158/1078-0432.CCR-05-1325
M. Landriscina, F. Maddalena, A. Fabiano, A. Piscazzi, O. La Macchia and M. Cignarelli, “Erlotinib Enhances the Proapoptotic Activity of Cytotoxic Agents and Synergizes with Paclitaxel in Poorly-Differentiated Thyroid Carcinoma Cells,” Anticancer Research, Vol. 30, No. 2, 2010, pp. 473-480.
F. Ciardiello, R. Bianco, V. Damiano, S. De Lorenzo, S. Pepe, S. De Placido, Z. Fan, J. Mendelsohn, A. Bianco and G. Tortora, “Antitumor Activity of Sequential Treatment with Topotecan and Anti-Epidermal Growth Factor Receptor Monoclonal Antibody C225,” Clinical Cancer Research, Vol. 5, No. 4, 1999, pp. 909-916.
K. D. Lynn, D. G. Udugamasooriya, C. L. Roland, D. H. Castrillon, T. J. Kodadek and R. A. Brekken, “GU81, a VEGFR2 Antagonist Peptoid, Enhances the Anti-Tumor Activity of Doxorubicin in the Murine MMTV-PyMT Transgenic Model of Breast Cancer,” BMC Cancer, Vol. 10, 2010. pp. 397. doi:10.1186/1471-2407-10-397
L. Zhang, D. Yu, D. J. Hicklin, J. A. Hannay, L. M. Ellis and R. E. Pollock, “Combined Anti-Fetal Liver Kinase 1 Monoclonal Antibody (Anti-VEGFR) and Continuous Low-Dose Doxorubicin Inhibits Angiogenesis and Growth of Human Soft Tissue Sarcoma Xenografts by Induction of Endothelial Cell Apoptosis” Cancer Research, Vol. 62, No. 7, 2002, pp. 2034-2042.
L. B. Shih, D. M. Goldenberg, H. Xuan, H. W. Lu, M. J. Mattes and T. C. Hall, “Internalization of an Intact Doxorubicin Immunoconjugate,” Cancer Immunology, Immunotherapy, Vol. 38, No. 2,1994, pp. 92-98. doi:10.1007/BF01526203
H. J. Hansen, G. L. Ong and H. Diril, “Internalization and Catabolism of Radiolabeled Antibodies to the MHC Class-II Invariant Chain by B-Cell Lymphomas,” Bio- chemical Journal, Vol. 320, 1996, pp. 293-300.
A. C. Stan, D. L. Radu, S. Casares, C. A. Bona, T. D. Brumeanu, “Antineoplastic Efficacy of Doxorubicin Enzymatically Assembled on Galactose Residues of a Monoclonal Antibody Specific for the Carcinoembryonic Antigen,” Cancer Research, Vol. 59, No. 1, 1999, pp. 115-121.
M. Pimm, V, M. A. Paul, T. Ogumuyiwa and R. W. Baldwin, “Biodistribution and Tumour Localization of a Daunomycin-Monoclonal Antibody Conjugate in Nude Mice and Human Tumour Xenografts,” Cancer Immunology, Immunotherapy, Vol. 27, No. 3, 1988, pp. 267-271.