International
Tables for
Crystallography
Volume F
Crystallography of biological macromolecules
Edited by M. G. Rossmann and E. Arnold

© International Union of Crystallography 2006
International Tables for Crystallography (2006). Vol. F. ch. 1.3, p. 21   | 1 | 2 |

Section 1.3.4.3.1. Cancers

W. G. J. Hola* and C. L. M. J. Verlindea

aBiomolecular Structure Center, Department of Biological Structure, Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195-7742, USA
Correspondence e-mail:  hol@gouda.bmsc.washington.edu

1.3.4.3.1. Cancers

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Over a hundred different cancers have been described and clearly the underlying defect, loss of control of cell division, can be the result of many different shortcomings in different cells. The research in this area proceeds at a feverish pace, yet the development, discovery and design of effective but safe anti-cancer agents are unbelievably difficult challenges. The modifications needed to turn a normal cell into a malignant one are very small, hence the chance of arriving at `true' anti-cancer drugs that exploit such small differences between normal and abnormal cells is exceedingly small. Nevertheless, such selective anti-cancer agents would leave normal cells essentially unaffected and are therefore the holy grail of cancer therapy. Few if any such compounds have been found so far, but cancer therapy is benefiting from a gradual increase in the number of useful compounds. Many have serious side effects, weaken the immune system and are barely tolerated by patients. However, they rescue large numbers of patients and hence it is of interest that many targets of these compounds, proteins and DNA molecules, have been structurally elucidated by crystallographic methods – often in complex with the cancer drug. The mode of action of many anti-cancer compounds is well understood, e.g. methotrexate targeting dihydrofolate reductase, and fluorouracil targeting thymidilate synthase. These are specific enzyme inhibitors acting along principles well known in other areas of medicine. Several anti-cancer drugs display unusual modes of action, such as:

  • (a) the DNA intercalators daunomycin (Wang et al., 1987[link]) and adriamycin (Zhang et al., 1993[link]);

  • (b) cisplatin, which forms DNA adducts (Giulian et al., 1996[link]);

  • (c) taxol, which not only binds to tubulin but also to bcl-2, thereby blocking the machinery of cancer cells in two entirely different ways (Amos & Lowe, 1999[link]);

  • (d) camptothecin analogues, such as irinotecan and topotecan, which have the unusual property of prolonging the lifetime of a covalent topoisomerase–DNA complex, generating major road blocks on the DNA highway and causing DNA breakage and cell death;

  • (e) certain compounds function as minor-groove binders, e.g. netropsin and distamycin (Kopka et al., 1985[link]);

  • (f) completely new drugs which were developed based on the structures of matrix metalloproteinases, purine nucleotide phosphorylase and glycinamide ribonucleotide formyltransferase and which are in clinical trials (Jackson, 1997[link]).

Meanwhile, it is sad that crystallography has not yet made any contribution to the molecular understanding of multi-drug resistance in cancer. The resistance is caused by cellular pumps that efficiently pump out the drugs, often leading to failed chemotherapy (Borst, 1999[link]). On the other hand, the structures of major oncogenic proteins such as p21 (DeVos et al.[link], 1988; Pai et al., 1989[link]; Krengel et al., 1990[link]; Scheffzek et al., 1997[link]) and p53 (Cho et al., 1994[link]; Gorina & Pavletich, 1996[link]) are of tremendous importance for future structure-based design of anti-neoplastic agents.

References

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