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Cytotoxic Drug Resistance Mechanisms.
  1. Chris Norbury

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    Brown R, Boger-Brown U, eds. ($89.00.) Humana Press, 1999. ISBN 0 896 036030 0.

    Cancer chemotherapy is not working, or at least it is not working as well as one would like. More often than not, intrinsic or acquired resistance of tumour cells to cytotoxic drugs renders such treatment ineffective. This book aims to equip those involved in basic and “translational” research with a repertoire of experimental approaches to this problem of anticancer drug resistance. The extent of the problem and the practical difficulties associated with using patients who have cancer as an “experimental system” are set out in an excellent opening chapter by Alan Anthoney and Stanley Kaye. This clinical perspective seemed fairly familiar, however, and I was more attracted by the remainder of the book, which is essentially a collection of laboratory protocols. These cover a wide range of techniques applicable to the usual molecular suspects, including P-glycoprotein and related drug transporters, p53, the Bcl-2 family, and glutathione conjugation. As the introductory chapter points out, it is often difficult to attribute clinical observations of drug resistance to any one of these high profile mechanisms. This could result from, in part at least, the small size of many of the relevant clinical studies, but it seems likely that additional molecular mechanisms of equal or greater importance remain to be identified. With this in mind, two chapters deal with in situ hybridisation, one technique that might help identify novel resistance mechanisms, where resistance is associated with genomic rearrangement. A panel of authors biased towards the USA (rather than the UK) would surely have contributed further chapters on the “information intensive” methods for the identification of novel resistance mechanisms favoured by the National Cancer Institute. Perhaps such chapters will be included in a revised edition, assuming that resistance to anticancer drugs will be providing a challenge to researchers for some years to come.

    The protocols themselves are set out in self contained chapters that span the broad range of personal styles inevitable in any multi-author volume. Refreshing honesty (or is it dry wit?) shines through here and there. Those thinking of setting up fluorescence in situ hybridisation (FISH) are advised to “visit a lab where the technique is done routinely”. No need to buy the book then—simply locate your local medical genetics unit (practical help is on hand here again—“such units are usually attached to hospitals and universities”). In the main, however, the protocols are easy to follow and highly detailed. Very precise sets of instructions (in the case of denaturing polyacrylamide gel electrophoresis, two different sets in two chapters) are frequently presented that, in many cases, would need to be adapted to suit the routine practices of the reader. For example, because laboratories increasingly have access to fluorescence based automated DNA sequencers, it seems unlikely that the radioactive labelling of PCR products (as recommended here for the analysis of microsatellite instability) will be an attractive option for many. Similarly, a chapter on measuring DNA–drug adducts in single cells is dominated by a painstaking (and to the uninitiated, incomprehensible) description of the operation of the particular image analysis software in use in the author's laboratory. This will be of little additional value to those already using this software (for whom the manual supplied with the software might be more appropriate) and of no value whatever to those using any of the numerous alternative software packages.

    But it would be churlish to dwell on these shortcomings, which if nothing else (along with some poor quality figures and a wanton disregard for proof reading) add a certain parochial charm. Like many investigators, ranging from those interested in the basic biology of cancer cells to those assessing responses to treatment at the cellular level in clinical material, I will find many of the protocols of lasting value. If only they were published in a more easily updatable and expendable format!