Introduction

Much of this book has supported the notion that cancer cells resistant to anti-cancer drugs arise via random undirected mechanisms. The basis of this conclusion is not an exhaustive study of in vivo and in vitro tumour systems treated with all available drugs but a matter of generalization from a large body of evidence including the results of experiments of the fluctuation test type. As our review in Chapter 4 showed, a positive result in a fluctuation test implies that there exists a source of variation that cannot be attributed to the sampling variation expected under the directed mutation model. In terms of two possible processes that may result in resistance, directed mutation and random mutation, the fluctuation test can point to the existence of random mutation but not to the absence of directed mutation. Furthermore, since the essence of the fluctuation test is quantitative rather than qualitative, results from such experiments apply to the most common mechanism for the development of resistance under the experimental conditions. It is well known in cancer that many distinct genetic alterations can lead to resistance; as a result, the fluctuation test will provide information about the one that occurs most frequently (unless two or more mechanisms give rise to resistant cells with a similar frequency, in which case results will relate to the combination of these mechanisms).

The question of possible directed mutation in E. coli

Many investigators have considered the origin of resistant subtypes in different systems.