Antitumor Drug Resistance (Handbook of Experimental Pharmacology, 72)

The study of tumour resistance to anticancer drugs has been the subject of many publications since the initial discovery of the phenomenon by J. H. Burchenal and colleagues in 1950. Many papers have been published since then reporting development of resistance to most of the well-known anticancer agents in many different animal tumour systems, both in vivo and in vitro. Many different mechanisms of resistance have been described, and it is clear that the tumour cell has a wide diversity of options in overcoming the cell-killing activity of these agents. Definition of the magnitude of the phenomenon in the clinic is, however, much more problematical, and it is with this in mind that the initial chapter, seeks to out­ line the problem as the clinicians see it. It appears that the phenomenon of true resistance to a drug, as the biochemist would recognise it, is an important cause of the failure which clinicians experience in treating the disease. The extent of the contribution of this phenomenon to the failure of treatment cannot easily be evaluated at the present time, but it is hoped that the development and application of new and more sophisticated techniques for the analysis of cellular sub­ populations may help to give a more exact estimate and to shed some light on the causes of failure of many of the present therapeutic techniques. Front Matter....Pages I-XXV Front Matter....Pages 1-1 Clinical Setting....Pages 3-21 Experimental Setting....Pages 23-36 Front Matter....Pages 37-37 Drug Disposition and Pharmacology....Pages 39-66 Immunological Changes....Pages 67-87 The Molecular Basis of Genetically Acquired Resistance to Purine Analogues in Cultured Mammalian Cells....Pages 89-98 Front Matter....Pages 99-99 Cell Cycle Perturbation Effects....Pages 101-141 Tumour Resistance and the Phenomenon of Inflammatory-Cell Infiltration....Pages 143-185 Flow Cytometric Methods for Studying Enzyme Activity in Populations of Individual Cells....Pages 187-203 Chromosome Studies....Pages 205-239 Alterations of Drug Transport....Pages 241-298 Cell Hybridisation....Pages 299-332 Front Matter....Pages 333-333 Drug Resistance and DNA Repair....Pages 335-369 Cyclic AMP and Prostaglandins....Pages 371-389 Properties of Mitochondria....Pages 391-402 Mechanism of “Resistance” Towards Specific Drug Groups....Pages 403-424 Nitrosoureas....Pages 425-442 Front Matter....Pages 443-443 Antipurines....Pages 445-493 Ribofuranose-containing Analogues of Uridine and Cytidine....Pages 495-513 5-Halogenated Pyrimidines and Their Nucleosides....Pages 515-549 Resistance to Amino Acid Analogs....Pages 551-568 Front Matter....Pages 443-443 Alkaloids....Pages 569-612 Front Matter....Pages 613-613 Folate Antagonists....Pages 615-631 Steroids....Pages 633-669 Front Matter....Pages 671-671 Collateral Sensitivity and Cross-Resistance....Pages 673-697 Back Matter....Pages 699-740 The study of tumour resistance to anticancer drugs has been the subject of many publications since the initial discovery of the phenomenon by J.H. Burchenal and colleagues in 1950. Many papers have been published since then reporting development of resistance to most of the well-known anticancer agents in many different animal tumour systems, both in vivo and in vitro. Many different mechanisms of resistance have been described, and it is clear that the tumour cell has a wide diversity of options in overcoming the cell-killing activity of these agents. Definition of the magnitude of the phenomenon in the clinic is, however, much more problematical, and it is with this in mind that the initial chapter, seeks to outƯ line the problem as the clinicians see it. It appears that the phenomenon of true resistance to a drug, as the biochemist would recognise it, is an important cause of the failure which clinicians experience in treating the disease. The extent of the contribution of this phenomenon to the failure of treatment cannot easily be evaluated at the present time, but it is hoped that the development and application of new and more sophisticated techniques for the analysis of cellular subƯ populations may help to give a more exact estimate and to shed some light on the causes of failure of many of the present therapeutic techniques