Skip to main content
SpringerLink
Log in

Drug-HPMA-HuIg Conjugates Effective Against Human Solid Cancer

  • Chapter
Polymer Drugs in the Clinical Stage

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 519))

Conclusion

N-(2-hydroxypropyl)methacrylamide copolymer (PHPMA)-bound doxorubicin conjugated with human Ig as a targeting moiety was used for the first time in the setting of metastatic breast cancer (patients E. G., J. K., K. R. and K.H.) and angiosarcoma (patient D. H) resistant to conventional cytotoxic chemotherapy. It was confirmed that Dox-PHPMA-Hulg conjugate is stable and doxorubicin remains in the peripheral blood mostly in its polymer-bound form. In patients E. G., J. K., K.R. and K.H. more than 116 biochemical and immunological parameters were tested in blood samples taken from the patients 24 h, 48 h, 72 h, 7 d, 14 d and 21, 28 and eight weeks after the treatment. In the patient E. G., 15 parameters had pathological values before the treatment. During the treatment, seven parameters dropped permanently or temporarily to a normal level and seven moved markedly towards the physiological value. While the number of peripheral blood reticulocytes was significantly decreased after the treatment with free doxorubicin, their number was stable or elevated after the treatment with Dox-PHPMA-Hulg conjugate. Increased absolute number of CD16+56+ and CD4+ cells in the peripheral blood and activation of NK and LAX cells in a human patients support the data previously obtained in experimental animals pointing to a dual role, i.e. the cytotoxic and immunomobilizing character of doxorubicin-PHPMA conjugates containing a targeting immunoglobulin moiety.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Maeda, H., and Matsumura, Y., 1987, Tumouritropic and lymphotropic principles of macromolecular drugs. CRC Crit. Rev. Ther. Drug Carrier Syst.6:193–210.

    Google Scholar 

  2. Suzuki, F., Pollard, R. B., Uchimura, S., Munakata, T., and Maeda, H., 1990, Role of natural killer cells and macrophages in the nonspecific resistance to tumors in mice stimulated with SMANCS, a polymer-conjugated derivative of neocarzinostatin. Cancer. Res. 50:3897–3904.

    PubMed  CAS  Google Scholar 

  3. Říhová, B., Strohalm, J., Kubáčková, K., Jelínková, M., Hovorka, O., Kovář, M., Plocová, D., Šírová, M., Śt’astný, M., Rozprimová, L., and Ulbrich, K., 2002, Acquired and specific immunological mechanisms co-responsible for efficacy of polymer-bound drugs. J. Control. Rel. 78:97–114.

    Google Scholar 

  4. Kopeček, J., Rejmanová, P., Strohalm, J., Ulbrich, K., Říhová, B., Chytrý, V., Lloyd, J.B., and Duncan, R., 1991, Synthetic polymeric drugs, US patent 5,037,883.

    Google Scholar 

  5. Říhová B., and Kopeček, J., 1985, Biological properties of targetable poly N-(2-hydroxypropyl) methacrylamide — antibody conjugates. J. Control. Rel. 2:289–310.

    Google Scholar 

  6. Duncan, R., Kopeěková-Rejmanová, P., Strohalm, J., Hume, I., Cable, H. C., Pohl, J., Lloyd, J. B., and Kopeček, J., 1987, Anticancer agents coupled to N-(2-hydroxypropyl)methacrylamide copolymers. 1. Evaluation of daunomycin and puromycin conjugates in vitro. Brit. J. Cancer 55:165–174.

    PubMed  CAS  Google Scholar 

  7. Říhová, B., Kopečková, P., Strohalm, J., Rossmann, P., Větvička, A., and Kopeček, J., 1988, Antibody-directed affinity therapy applied to the immune system: In vivo effectiveness and limited toxicity of daunomycin conjugated to HPMA copolymers and targeting antibody. Clin. Immunol. Immunopathol. 46: 100–114.

    PubMed  Google Scholar 

  8. Duncan, R., Kopečková, P., Strohalm, J., Hume, I. C., Lloyd, J. B., and Kopečk, J., 1988, Anticancer agents coupled to N-(2-hydroxypropyl)methacrylamide copolymers. II. Evaluation of daunomycin conjugates in vivo against L1210 leukaemia. Brit. J. Cancer 57: 147–156.

    PubMed  CAS  Google Scholar 

  9. Duncan, R., Hume, I. C., Kopečková, P., Ulbrich, K., Strohalm, J., and Kopeček, J., 1989, Anticancer agents coupled to N-(2-hydroxypropyl)methacylamide copolymers. 3. Evaluation of adriamycin conjugates against mouse leukaemia L1210 in vivo. J. Contr. Rel. 10: 51–63.

    Article  CAS  Google Scholar 

  10. Cassidy, J., Duncan, R., Morrison, G. J., Strohalm, J., Plocová, D., Kopeček, J., and Kaye, S.B., 1989, Activity of N-(2-hydroxypropyl)methacrylamide copolymers containing daunomycin against a rat tumour model. Biochem. Pharmacol. 38: 875–879.

    Article  PubMed  CAS  Google Scholar 

  11. Duncan, R., 1992, Drug-polymer conjugates: potential for improved chemotherapy. Anticancer Drugs 3: 175–210.

    PubMed  CAS  Google Scholar 

  12. Říhová., Krinick, N. L., and Kopeček, J., 1993, Targetable photoactivatable drugs. 3. In vitro efficacy of polymer bound chlorin e 6 toward human hepatocarcinoma cell line (PLC/PRF/5) targeted with galactosamine and to mouse splenocytes targeted with anti-Thy 1.2 antibodies. J. Contr. Rel. 25: 71–87.

    Google Scholar 

  13. Seymour, L.W., 1994, Soluble polymers for lectin-mediated drug targeting. Adv. Drug Delivery Rev. 14: 89–111.

    Article  CAS  Google Scholar 

  14. Říhová B., 1996, Biocompatibility of biomaterials: hemocompatibility, immunocompatibility and biocompatibility of solid polymeric materials and soluble targetable polymeric carriers. Adv. Drug Delivery Reviews 21:157–176.

    Google Scholar 

  15. Říhová, B., Strohalm, J., Plocová, D., Šubr, V., Šrogl, J., Jelínková, M., Šírová, M., and Ulbrich, K.,1996, Cytotoxic and cytostatic effects of anti-Thy 1.2 targeted doxorubicin and cyclosporin A. J. Control. Rel. 40: 303–319.

    Google Scholar 

  16. Peterson, C. M., Lu, J. M., Sun, Y., Peterson, C.A., Shiah, J.-G., Straight, R. C., and Kopeček, J., 1996, Combination chemotherapy and photodynamic therapy with N-(2-hydroxypropyl)methacrylamide copolymer-bound anticancer drugs inhibit human ovarian carcinoma heterotransplanted in nude mice. Cancer Res. 56: 3980–3985.

    PubMed  CAS  Google Scholar 

  17. Minko, T., Kopečková, P., and Kopeček, J., 2000, Efficacy of chemotherapeutic action of HPMA copolymer-bound doxorubicin in a solid tumor model of ovarian carcinoma. Int. J. Cancer 86: 108–117.

    Article  PubMed  CAS  Google Scholar 

  18. Říhová, B., Jelínková, M., Strohalm, J., Šubr, V., Plocová, D., Hovorka, O., Novák, M., Plundrová, D., Germano, Y., and Ulbrich, K., 2000, Polymeric drugs based on conjugates of synthetic and natural macromolecules. II. Anti-cancer activity of antibody or (Fab’) 2 -targeted conjugates and combined therapy with immunomodulators. J. Control. Rel. 64: 241–26.

    Google Scholar 

  19. Říhová, B., Jelínková, M., Strohalm, J., Št’astný, M., Hovorka, O., Plocová, D., Kováf, M., Dráberová, L., and Ulbrich, K., 2000, Antiproliferative effect of a lectin-and anti-Thy-1.2 antibody-targeted HPMA copolymer-bound doxorubicin on primary and metastatic human colorectal carcinoma and on human colorectal carcinoma transfected with mouse Thy-1.2 gene. Bioconjugate Chemistry 11: 664–673.

    PubMed  Google Scholar 

  20. Rejmanová, P., Kopeček, J., Duncan, R., and Lloyd, J.B., 1985, Stability in rat plasma and serum of lysosomally degradable oligopeptide sequences in N-(2-hydroxypropyl)methacrylamide copolymers. Biomaterials 6: 45–48.

    PubMed  Google Scholar 

  21. Kopeček, J., 1984, Controlled biodegradability of polymers — a key to drug delivery systems. Biomaterials 5: 19–25.

    PubMed  Google Scholar 

  22. Minko, T., Kopečková, P., Pozharov, V., and Kopeček, J., 1998, HPMA copolymer bound adriamycin overcomes MDR1 gene encoded resistance in a human ovarian carcinoma cell line. J. Contr. Rel. 54: 223–233.

    Article  CAS  Google Scholar 

  23. Říhová, B., Kopečková, P., Št’astný, M., Strohalm, J., Plocová, D., Ulbrich, K., and Říhová, B., 1999, A possibility to overcome P-glycoprotein (PGP)-mediated multidrug resistance by antibody-targeted drugs conjugated to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carrier. Eur. J. Cancer 35: 459–466.

    Google Scholar 

  24. Říhová, B., Kopečková, P., Strohalm, J., Rossmann, P., Větvička, V., and Kopeček, J., 1988, Antibody-directed affinity therapy applied to the immune system: In vivo effectiveness and limited toxicity of daunomycin conjugated to HPMA copolymers and targeting antibody. Clin. Immunol. Immunopathol. 46: 100–114.

    PubMed  Google Scholar 

  25. Říhová, B., Jegorov, A., Strohalm, J., Mat’ha, V., Rossmann, P., Fornùsek, L., and Ulbrich, K., 1992, Antibody-targeted cyclosporin A. J. Control. Rel. 19: 25–39.

    Google Scholar 

  26. Yeung, T. K., Hopewell, J. W., Simmonds, R. H., Seymour, L. W., Duncan, R., Bellini, O., Grandi, M., Spreafico, F., Strohalm, J., and Ulbrich, K., 1991, Reduced cardiotoxicity of doxorubicin administered in the form of N-(2-hydroxypropyl)methacrylamide copolymer conjugates: an experimental study in the rat. Cancer Chemother. Pharmacol. 29: 105–111.

    Article  PubMed  CAS  Google Scholar 

  27. Říhová, B., Bilej, M., Větvička, V., Ulbrich, K., Strohalm, J., Kopeček, J., and Duncan, R., 1989, Biocompatibility of N-(2-hydroxypropyl)methacrylamide copolymers containing adriamycin. Biomaterials 10: 335–342.

    PubMed  Google Scholar 

  28. Rossmann, P., Říhová, B., Strohalm, J., and Ulbrich, K., 1997, Morphology of rat kidney and thymus after native and antibody-coupled cyclosporin A application (Reduced toxicity of targeted drug). Folia Microbiol. 42: 277–287.

    CAS  Google Scholar 

  29. Št’astný, M., Ulbrich, K., Strohalm, J., Rossmann, P., and Říhová, B., 1997, Abnormal differentiation of thymocytes induced by free cyclosporine is avoided when cyclosporine bound to N-(2-hydroxypropyl)methacrylamide copolymer carrier is used. Transplantation 63: 1818–1827.

    Google Scholar 

  30. Penn, I., 1993, The effect of immunosuppression on preexisting cancers. Transplant Proc. 25, 1380–1382.

    PubMed  CAS  Google Scholar 

  31. Shoenfeld, Y., and Fishman, P., 1999, Gamma-globulin inhibits tumor spread in mice. Int. Immunology 11: 1247–1251.

    CAS  Google Scholar 

  32. Torchilin, V.P., lakounbov, L.Z., Samokhin, G. P., Rammohan, R., Mongayat, D. A., and Lukyanov, A. L., 2001, Tumor cell surface-bound nucleosomes: universal molecular targets for tumoricidal autoantibodies. J.Control. Rel. 74: 373–375.

    Google Scholar 

  33. Ulbrich, K., Šubr, V., Strohalm, J., Plocová, D., Jelínková, M., and Říhová, B., 2000, Polymeric drugs based on conjugates of synthetic and natural macromolecules. I.Synthesis and physicochemical characterization. J. Control. Rel. 64: 63–79.

    CAS  Google Scholar 

  34. RŘíhová, B., Strohalm, J., Kubáčková, K., Jelínková, M., Rozprimová, L., Šírová, M., Plocová, D., Etrych, T., Mrkvan, T., Kovář, M., Pokorná, J., Št’astný, M., and Ulbrich, K., Dual activity of PHPMA-based doxorubicin containing human Ig in four patients with disseminated breast cancer, submitted

    Google Scholar 

  35. Steel, D., and Whitehead, A.S., 1994, The major acute phase reactants: C-reactive protein, serum amyloid P component and serum amyloid A protein, Immunology Today 15: 81–88.

    Article  PubMed  CAS  Google Scholar 

  36. Zach, O., Kasparu, H., Krieger, O., Hehenwarter, W., Girschikofsky, M., and Lutz, D., 1999, Detection of circulating mammary carcinoma cells in the peripheral blood of breast cancer patients via a nested reverse transcriptase polymerase chain reaction assay for mammaglobin mRNA, J. Clin. Oncol. 17: 2015–2019.

    PubMed  CAS  Google Scholar 

  37. Barber, M. D., Ross, J.A., and Fearon, K.C., 1999, Changes in nutritional, functional, and inflammatory markers in advanced pancreatic cancer, Nutr. Cancer 35:106–110.

    Article  PubMed  CAS  Google Scholar 

  38. Lauerová, L., Dušek, L., Šimíčková, M., Rovný, F., Spurný, V., Rovný, F., Slampa, P., Žaloudík, J., Rejthar, A., Wotke, J., and Kopeček, J., 1999, Renal cell carcinomaassociated immune impairment that may interfere with the response to cytokine therapy. Neoplasma 46:141–149.

    PubMed  Google Scholar 

  39. Nozoe, T., Matsumata, T., and Sugimachi, K., 2000, Preoperative elevation of serum Creactive protein is related to impaired immunity in patients with colorectal cancer. Am. J. Clin. Oncol. 23: 263–266.

    PubMed  CAS  Google Scholar 

  40. Berois, N., Varangot, M., Aizen, B., Estrugo, R., Zarantonelli, L., Fernandez, P., Krygier, G., Simonet, F., Barrois, E., Muse, I., and Osinaga, E., 2000, Molecular detection of cancer cells in bone marrow and peripheral blood of patients with operable breast cancer. Comparison of CD19, MUC1 and CEA using RT-PCR. Eur. J. Cancer 36:717–723.

    Article  PubMed  CAS  Google Scholar 

  41. Lumachi, F., Brandes, A. A., Boccagni, P., Polistina, F., Favia, G., and D’ Amico, D. F., 1999, Long-term follow up study in breast cancer patients using serum tumor markers CEA and CA 15-3. Anticancer Res. 19: 4485–4489.

    PubMed  CAS  Google Scholar 

  42. Huang, J., Hardy, J. D., Sun, Y., and Shively, J. E., 1999, Essential role of biliary glycoprotein (CD66a) in morphogenesis of the human mammary epithelial cell line MCF10F. J.Cell Sci.112 (Pt 23): 4193–4205.

    PubMed  CAS  Google Scholar 

  43. Montelli, T. C., Peracoli, M. T., Gabarra, R. C., Soares, A. M., and Kurokawa, C. S., 2001, Familial cancer: depressed NK-cell cytotoxicity in healthy and cancer affected members. Arq. Neuropsiquiatr. 59:6–10.

    PubMed  CAS  Google Scholar 

  44. Sephton, S.E., Sapolsky, R.M., Kraemer, H.C., and Spiegel, D., 2000, Diurnal cortisol rhythm as a predictor of breast cancer survival, J. Natl. Cancer Inst. 92: 994–1000.

    Article  PubMed  CAS  Google Scholar 

  45. Julyan, P. J., Seymour, L. W., Ferry, D. R., Daryani, S., Boivin, Ch. M., Doran, J., David, M., Anderson, D., Christodoulou, Ch., Young, A. M., Hesselwood, S., and Kerr, D.J., 1999, Preliminary clinical study of the distribution of HPMA copolymers bearing doxorubicin and galactosamine. J. Control. Rel. 57: 281–290.

    CAS  Google Scholar 

  46. Thomson, A. H., Vasey, P. A., Murray, L. S., Cassidy, J., Fraier, D., Frigerio, E., and Twelves, C., 1999, Population pharmacokinetics in phase I drug development: a phase I study of PK1 in patients with solid tumors. British J.Cancer 81: 99–107.

    CAS  Google Scholar 

  47. Říhová, B., Vereš, K., Formúsek, L., Ulbrich, K., Strohalm, J., Větvička, V., Bilej, M., and Kopeček, J., 1989, Action of the polymeric prodrugs based on N-(2-hydroxypropyl)methacrylamide. 2. Body distribution and T cell accumulation of 125DNM. J. Control. Rel. 10: 37–49.

    Google Scholar 

  48. Flanagan, P. A., Duncan, R., Říhová, B., Šubr, V., and Kopeček, J., 1990, Immunogenicity of protein-N-(2-hydroxypropyl)methacrylamide conjugates in A/J and B10 mice. J. Bioact. Compat. Polymers 5: 151–166.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Microbiology, Academy of Sciences of the Czech Republic, Vldeňská, 1083, 142 20, Prague 4, Czech Republic

    Blanka ŘÍHovÁ, MarkÉTa JelÍNkovÁ, Milada ŠÍRov Á, TomÁŠ Mrkvan, Marek KovÁŘ & JindŘIŠKa PokornÁ

  2. Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovsky sq., 2, 16206, Prague 6, Czech Republic

    JiŘÍ Strohalm, Dana PlocovÁ, TomÁŠ Etrych & Karel Ulbrich

  3. The University Hospital Motol, V úvalu, 84, 150 18, Prague 5, Czech Republic

    KateŘIna KubÁČKovÁ

  4. AGILAB-Biochemical and Immunological Laboratory, Jeseniova, 101, 130 00, Prague 3, Czech Republic

    LaĎKa RozprimovÁ

Authors
  1. Blanka ŘÍHovÁ
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. JiŘÍ Strohalm
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. KateŘIna KubÁČKovÁ
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. MarkÉTa JelÍNkovÁ
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. LaĎKa RozprimovÁ
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Milada ŠÍRov Á
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dana PlocovÁ
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. TomÁŠ Mrkvan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marek KovÁŘ
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. JindŘIŠKa PokornÁ
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. TomÁŠ Etrych
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Karel Ulbrich
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Kumamoto University School of Medicine, Kumamoto, Japan

    Hiroshi Maeda

  2. University of Nebraska Medical Center, Omaha, Nebraska

    Alexander Kabanov

  3. University of Tokyo, Tokyo, Japan

    Kazunori Kataoka

  4. Tokyo Women’s Medical College, Tokyo, Japan

    Teruo Okano

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Kluwer Academic Publishers

About this chapter

Cite this chapter

ŘÍHovÁ, B. et al. (2004). Drug-HPMA-HuIg Conjugates Effective Against Human Solid Cancer. In: Maeda, H., Kabanov, A., Kataoka, K., Okano, T. (eds) Polymer Drugs in the Clinical Stage. Advances in Experimental Medicine and Biology, vol 519. Springer, Boston, MA. https://doi.org/10.1007/0-306-47932-X_8

Download citation

  • DOI: https://doi.org/10.1007/0-306-47932-X_8

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-306-47471-2

  • Online ISBN: 978-0-306-47932-8

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation