Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1987 Jun;84(12):4288–4292. doi: 10.1073/pnas.84.12.4288

A monoclonal antibody-Pseudomonas toxin conjugate that specifically kills multidrug-resistant cells.

D J FitzGerald, M C Willingham, C O Cardarelli, H Hamada, T Tsuruo, M M Gottesman, I Pastan
PMCID: PMC305070  PMID: 3495806

Abstract

One form of multidrug resistance is due to the expression of a 170-kDa energy-dependent drug efflux pump called P-glycoprotein in the plasma membranes of human cancer cells. We have prepared conjugates of Pseudomonas toxin with the anti-P-glycoprotein monoclonal antibody MRK-16. These anti-P-glycoprotein-toxin conjugates specifically kill multidrug-resistant human KB cells. Similar conjugates could be useful in cancer therapy to reduce or eliminate multidrug-resistant tumor populations in tumors intrinsically resistant to chemotherapy or in populations that become resistant during combination chemotherapy.

Full text

PDF
4288

Images in this article

4289Image
on p.4289
4289Image
on p.4289
4289Image
on p.4289
4289Image
on p.4289
4289Image
on p.4289
4289Image
on p.4289

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akiyama S., Fojo A., Hanover J. A., Pastan I., Gottesman M. M. Isolation and genetic characterization of human KB cell lines resistant to multiple drugs. Somat Cell Mol Genet. 1985 Mar;11(2):117–126. doi: 10.1007/BF01534700. [DOI] [PubMed] [Google Scholar]
  2. Beck W. T., Mueller T. J., Tanzer L. R. Altered surface membrane glycoproteins in Vinca alkaloid-resistant human leukemic lymphoblasts. Cancer Res. 1979 Jun;39(6 Pt 1):2070–2076. [PubMed] [Google Scholar]
  3. Biedler J. L., Riehm H. Cellular resistance to actinomycin D in Chinese hamster cells in vitro: cross-resistance, radioautographic, and cytogenetic studies. Cancer Res. 1970 Apr;30(4):1174–1184. [PubMed] [Google Scholar]
  4. Chen C. J., Chin J. E., Ueda K., Clark D. P., Pastan I., Gottesman M. M., Roninson I. B. Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell. 1986 Nov 7;47(3):381–389. doi: 10.1016/0092-8674(86)90595-7. [DOI] [PubMed] [Google Scholar]
  5. Cornwell M. M., Gottesman M. M., Pastan I. H. Increased vinblastine binding to membrane vesicles from multidrug-resistant KB cells. J Biol Chem. 1986 Jun 15;261(17):7921–7928. [PubMed] [Google Scholar]
  6. Cornwell M. M., Pastan I., Gottesman M. M. Certain calcium channel blockers bind specifically to multidrug-resistant human KB carcinoma membrane vesicles and inhibit drug binding to P-glycoprotein. J Biol Chem. 1987 Feb 15;262(5):2166–2170. [PubMed] [Google Scholar]
  7. Cornwell M. M., Safa A. R., Felsted R. L., Gottesman M. M., Pastan I. Membrane vesicles from multidrug-resistant human cancer cells contain a specific 150- to 170-kDa protein detected by photoaffinity labeling. Proc Natl Acad Sci U S A. 1986 Jun;83(11):3847–3850. doi: 10.1073/pnas.83.11.3847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. FitzGerald D. J., Trowbridge I. S., Pastan I., Willingham M. C. Enhancement of toxicity of antitransferrin receptor antibody-Pseudomonas exotoxin conjugates by adenovirus. Proc Natl Acad Sci U S A. 1983 Jul;80(13):4134–4138. doi: 10.1073/pnas.80.13.4134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. FitzGerald D. J., Waldmann T. A., Willingham M. C., Pastan I. Pseudomonas exotoxin-anti-TAC. Cell-specific immunotoxin active against cells expressing the human T cell growth factor receptor. J Clin Invest. 1984 Sep;74(3):966–971. doi: 10.1172/JCI111516. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. FitzGerald D. J., Willingham M. C., Pastan I. Antitumor effects of an immunotoxin made with Pseudomonas exotoxin in a nude mouse model of human ovarian cancer. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6627–6630. doi: 10.1073/pnas.83.17.6627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fojo A. T., Ueda K., Slamon D. J., Poplack D. G., Gottesman M. M., Pastan I. Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci U S A. 1987 Jan;84(1):265–269. doi: 10.1073/pnas.84.1.265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gerlach J. H., Endicott J. A., Juranka P. F., Henderson G., Sarangi F., Deuchars K. L., Ling V. Homology between P-glycoprotein and a bacterial haemolysin transport protein suggests a model for multidrug resistance. Nature. 1986 Dec 4;324(6096):485–489. doi: 10.1038/324485a0. [DOI] [PubMed] [Google Scholar]
  13. Gros P., Ben Neriah Y. B., Croop J. M., Housman D. E. Isolation and expression of a complementary DNA that confers multidrug resistance. Nature. 1986 Oct 23;323(6090):728–731. doi: 10.1038/323728a0. [DOI] [PubMed] [Google Scholar]
  14. Gros P., Croop J., Housman D. Mammalian multidrug resistance gene: complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell. 1986 Nov 7;47(3):371–380. doi: 10.1016/0092-8674(86)90594-5. [DOI] [PubMed] [Google Scholar]
  15. Hamada H., Tsuruo T. Functional role for the 170- to 180-kDa glycoprotein specific to drug-resistant tumor cells as revealed by monoclonal antibodies. Proc Natl Acad Sci U S A. 1986 Oct;83(20):7785–7789. doi: 10.1073/pnas.83.20.7785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hwang J., Fitzgerald D. J., Adhya S., Pastan I. Functional domains of Pseudomonas exotoxin identified by deletion analysis of the gene expressed in E. coli. Cell. 1987 Jan 16;48(1):129–136. doi: 10.1016/0092-8674(87)90363-1. [DOI] [PubMed] [Google Scholar]
  17. Kartner N., Riordan J. R., Ling V. Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science. 1983 Sep 23;221(4617):1285–1288. doi: 10.1126/science.6137059. [DOI] [PubMed] [Google Scholar]
  18. Ling V., Thompson L. H. Reduced permeability in CHO cells as a mechanism of resistance to colchicine. J Cell Physiol. 1974 Feb;83(1):103–116. doi: 10.1002/jcp.1040830114. [DOI] [PubMed] [Google Scholar]
  19. Pastan I., Willingham M. C., FitzGerald D. J. Immunotoxins. Cell. 1986 Dec 5;47(5):641–648. doi: 10.1016/0092-8674(86)90506-4. [DOI] [PubMed] [Google Scholar]
  20. Shen D. W., Cardarelli C., Hwang J., Cornwell M., Richert N., Ishii S., Pastan I., Gottesman M. M. Multiple drug-resistant human KB carcinoma cells independently selected for high-level resistance to colchicine, adriamycin, or vinblastine show changes in expression of specific proteins. J Biol Chem. 1986 Jun 15;261(17):7762–7770. [PubMed] [Google Scholar]
  21. Shen D. W., Fojo A., Chin J. E., Roninson I. B., Richert N., Pastan I., Gottesman M. M. Human multidrug-resistant cell lines: increased mdr1 expression can precede gene amplification. Science. 1986 May 2;232(4750):643–645. doi: 10.1126/science.3457471. [DOI] [PubMed] [Google Scholar]
  22. Ueda K., Cardarelli C., Gottesman M. M., Pastan I. Expression of a full-length cDNA for the human "MDR1" gene confers resistance to colchicine, doxorubicin, and vinblastine. Proc Natl Acad Sci U S A. 1987 May;84(9):3004–3008. doi: 10.1073/pnas.84.9.3004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ueda K., Cornwell M. M., Gottesman M. M., Pastan I., Roninson I. B., Ling V., Riordan J. R. The mdr1 gene, responsible for multidrug-resistance, codes for P-glycoprotein. Biochem Biophys Res Commun. 1986 Dec 30;141(3):956–962. doi: 10.1016/s0006-291x(86)80136-x. [DOI] [PubMed] [Google Scholar]
  24. Willingham M. C., Cornwell M. M., Cardarelli C. O., Gottesman M. M., Pastan I. Single cell analysis of daunomycin uptake and efflux in multidrug-resistant and -sensitive KB cells: effects of verapamil and other drugs. Cancer Res. 1986 Nov;46(11):5941–5946. [PubMed] [Google Scholar]
  25. Willingham M. C., FitzGerald D. J., Pastan I. Pseudomonas exotoxin coupled to a monoclonal antibody against ovarian cancer inhibits the growth of human ovarian cancer cells in a mouse model. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2474–2478. doi: 10.1073/pnas.84.8.2474. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES