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Cancer Immunology, Immunotherapy

, Volume 32, Issue 5, pp 331–334 | Cite as

Inhibition of human renal cancer by monoclonal-anti-body-linked methotrexate in an ascites tumor model

  • M. Singh
  • T. Ghose
  • J. Kralovec
  • A. H. Blair
  • P. Belitsky
Short communication

Summary

The monoclonal antibody DAL K29 against a cell-surface antigen associated with a human renal cell carcinoma was covalently linked to the antifolate methotrexate with full retention of antibody activity and partial retention of drug activity. Using an ascites tumor model, developed after intraperitoneal (i.p.) inoculation of 5 × 106 cells of the human kidney cancer line Caki-1 per pristane-primed nude mouse, we showed that the methotrexate-Dal-K29 conjugate was a more potent tumor inhibitor (P <0.0005) of human renal cell carcinoma (which is resistant to currently available modalities including chemotherapy) than the drug or mAb alone, the drug linked to an isotype-matched nontumor-specific IgG or a mixture of the drug and the mAb. Only the conjugate could produce tumor-free survival in a proportion of the mice during the period of observation (i.e. 150 days after tumor inoculation).

Key words

Immunoconjugate Monoclonal antibody Renal cell carcinoma 

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References

  1. 1.
    Bracken RB (1987) Renal carcinoma: clinical aspects and therapy. Semin Roentgenol 22: 241Google Scholar
  2. 2.
    Fogh J, Trempe G (1975) New human tumor cell lines. In: Fogh J (ed) Human tumor cells in vitro. Plenum, New York, p 115Google Scholar
  3. 3.
    Garnick MB, Richie JP (1988) Primary neoplasms of the kidney and renal pelvis. In: Schrier RW (ed) Disease of the kidney. Little Brown, Boston, p 863Google Scholar
  4. 4.
    Gerhard W, Croce CM, Lopes D, Koprowski H (1978) Repertoire of antiviral antibodies expressed by somatic cell hybrids. Proc Natl Acad Sci USA 75: 1510Google Scholar
  5. 5.
    Ghose T, Blair AH (1987) Design of cytotoxic agent-antibody conjugates. CRC Crit Rev Ther Drug Carrier Syst 3: 263Google Scholar
  6. 6.
    Ghose T, Guclu A, Faulkner J, Tai J (1977) In vivo suppression of EL 4 lymphoma by rabbit antitumor sera. J Natl Cancer Inst 58: 693Google Scholar
  7. 7.
    Ghose T, Blair AH, Kralovec J, Mammen M, Uadia P (1988) Synthesis and testing of antibody-antifolate conjugates for drug targeting. In: Rodwell JD (ed) Antibody-mediated delivery systems. Dekker, New York, p 81Google Scholar
  8. 8.
    Kaplan P, Meier EL (1958) Nonparametric estimations from incomplete organizations. J Am Stat Assoc 53: 457Google Scholar
  9. 9.
    Kralovec J, Singh M, Mammen M, Blair AH, Ghose T (1989) Synthesis of site-specific methotrexate-IgG conjugates. Cancer Immunol Immunother 29: 293Google Scholar
  10. 10.
    Kulkarni PN, Blair AH, Ghose T (1981) Covalent binding of methotrexate to immunoglobulins and the effect of antibody-linked drug on tumor growth in vivo. Cancer Res 41: 2700Google Scholar
  11. 11.
    Linehan WM (1988) Renal cell carcinoma (editorial) J Urol 139: 340Google Scholar
  12. 12.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193: 165Google Scholar
  13. 13.
    Luner SJ, Ghose T, Chatterjee S, Cruz HN, Belitsky P (1986) Monoclonal antibodies to kidney and tumor-associated surface antigens of human renal cell carcinoma. Cancer Res 46: 5816Google Scholar
  14. 14.
    Peterson DL, Gleisner JM, Blakley RL (1975) Bovine liver dihydrofolate reductase: purification and properties of the enzyme. Biochemistry 14: 5261Google Scholar
  15. 15.
    Singh M, Ghose T, Faulkner G, Kralovec J, Mezi M (1989) Targeting of methotrexate-containing liposomes with a monoclonal antibody against human renal cancer. Cancer Res 49: 3976Google Scholar
  16. 16.
    Singh M, Kralovec J, Mezei M, Ghose T (1989) Inhibition of human renal cancer by methotrexate linked to a monoclonal antibody. J Urol 141: 428Google Scholar
  17. 17.
    Uadia PO, Blair AH, Ghose T (1988) Hydrolysis of methotrexateimmunoglobulin conjugates by liver homogenates and characterization of catabolites. Cancer Chemother Pharmacol 22: 175Google Scholar
  18. 18.
    Vaage J (1971) Concomitant immunity and specific depression of immunity by residual or reinjected syngeneic tumor tissue. Cancer Res 31: 1655Google Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • M. Singh
    • 1
  • T. Ghose
    • 1
  • J. Kralovec
    • 1
  • A. H. Blair
    • 1
  • P. Belitsky
    • 1
  1. 1.Departments of Pharmacy, Pathology, Biochemistry and UrologyDalhousie University and Victoria General Hospital, College St.HalifaxCanada

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