Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Introduction to resistance to anticancer agents

Oncogene volume 22, pages 7262–7264 (2003)Cite this article

Once inside the cell, the activity of drugs that require activation can be impaired by loss of specific enzymatic activities involved in their metabolic activation, as in the case of the metabolism of nucleoside analogs to cytotoxic nucleotide analogs (e.g., AraC). Certain agents can also be enzymatically inactivated, as in the case of methylation of thiopurine nucleobase analogs by thiopurine methyltransferase (TPMT). Cellular targets can also be altered, either by increased expression levels, or by mutations, such that they are less susceptible to inhibition, as in the case of camptothecins (topoisomerase I), epipodophyllotoxins (toposimerase II) antifolates (dihydrofolate reductase), fluoropyrimidines (thymidylate synthetase) and Gleevec (BCR-ABL). Once a cellular target is damaged, resistance factors can attenuate the capacity of a cell to undergo apoptosis (i.e., loss of p53 and cell cycle checkpoints). Another class of resistance involves factors that influence the ability of the cell to repair damaged macromolecules. Examples of this include loss of mismatch repair enzymes, which appears to confer resistance to fluoropyrimidines, or inactivation of MGMT, which confers enhanced sensitivity to certain alkylating agents. Each of these classes of resistance mechanisms is described in this issue.

As many of the best-characterized drug resistance mechanisms were elucidated from investigations of cell lines made highly resistant by stepwise selection in drug, and largely involve factors that influence the extent to which agents interact with their immediate cellular targets (mechanisms 1 and 2 in Figure 1), focusing on these mechanisms tends to lead to a ‘drug-centric’ perspective, and it is easy to lose track of the fact that clinical drug resistance is a manifestation of cancer. An informative way to illustrate this notion is to point out the clinical observation that while it is anticipated that even highly sensitive cancers, such as leukemias, lymphomas and small cell lung cancer, will frequently become resistant during the course of treatment, it is also anticipated that the patient's drug-sensitive tissues (i.e., bone marrow and mucosal surfaces of the alimentary tract) will not only not become resistant, but may in fact become increasingly depleted during therapy and eventually limit treatment options (Chu and DeVita, 2001). Thus, the somatic mutations and genomic plasticity associated with cancer are the foundation of drug resistance, be it acquired or intrinsic. In the circumstance of normal tissues, resistance does not arise, because the mutation rate is too low to permit defects in the genetic elements that control sensitivity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  • Chu E and DeVita VT . (2001). Cancer: Principles and Practice of Oncology. DeVita VT, Hellman S and Rosenberg SA (eds). Lippincott: Philadelphia, pp. 289–306.

    Google Scholar 

  • Knudson AG . (2001). Nat. Rev. Cancer, 1, 157–162.

Download references

Acknowledgements

I thank Dr Michael Gottesman for helpful discussions on the content of this issue, and for suggesting the title. This work was supported by NIH Grants CA73728 (to GDK) and CA06927 to the Fox Chase Cancer Center, and by an appropriation from the Commonwealth of Pennsylvania.

Author information

Authors and Affiliations

  1. Medical Science Division, Fox Chase Cancer Center, Philadelphia, 19111, PA, USA

    Gary D Kruh

Authors
  1. Gary D Kruh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gary D Kruh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kruh, G. Introduction to resistance to anticancer agents. Oncogene 22, 7262–7264 (2003). https://doi.org/10.1038/sj.onc.1206932

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206932

Keywords

This article is cited by

Search

Advanced search

Quick links