Can cancer chemotherapy enhance the malignant behaviour of tumours?

Abstract

Cancer chemotherapy is currently undergoing an intensive reappraisal because of its unimpressive performance against the major common cancers. There are a number of possible reasons for this lack of success; one considered here is that under some circumstances anti-neoplastic drug treatment actually increases the malignant behaviour of tumours. Support for this idea comes mainly from experimental studies in which drug treatments increased metastatic spread. Investigation of this phenomenon shows that drug induced modifications of the host, including immunosuppression and vascular damage, can indeed facilitate metastasis. In addition, new data are presented demonstrating that the direct action of drugs on the tumour cells themselves can have similar enhancing effects. The possible mechanisms underlying such direct effects are discussed and the ability of anti-cancer drugs to cause genetic mutations, amplify genes, and alter gene expression are considered. While the nature and extent of this facilitation of tumour malignancy is not fully understood, it is suggested that this possibility should be considered in the design of treatment protocols.

Drug-target interactions: only the first step in the commitment to a programmed cell death?

“…This aspect of a cellular 'reaction' to the formation of a drug receptor complex, and/or its sequellae, could be viewed as an 'adaptive response'. If apoptosis is viewed as one of the adaptive response repertoires of the cell, alongside the initiation of alternative pathways such as differentiation, the induction of a drug resistance phenotype -which in certain cases may be transient (Lazo & Basu, 1991), the induction of mechanisms of repair, or drug-induced increases in metastatic potential (McMillan & Hart, 1987), then not surprisingly the outcome of drug therapy will be determined by the response of the cell, according to its phenotype, rather than by the nature of the primary drug-target interaction alone (see Figure 1). Some cells, it seems, may be harder to kill than others, no matter how ingenious the strategy or how novel the drug or drug target, because they have an enhanced survival potential.…”

Targeted chemotherapy against intraperitoneally disseminated colon carcinoma using a cationized gelatin–conjugated HVJ envelope vector

“…In particular, metastatic cancer involving multiple foci and microscopic cancers are hard to treat, and prevention of recurrence remains a difficult problem in cancer therapy (1). Antitumor immunotherapy holds great promise; however, a number of obstacles have been encountered in the course of its development (2,3).…”

Differences in resistance to 5-fluorouracil as a function of cell cycle delay and not apoptosis

“…It has been postulated that the outcome of drug therapy will be determined by the response of the cell, according to its phenotype, rather than by the nature of the primary drug target interaction alone (Dive and Hickman, 1991). The response of the cell can manifest itself in several ways including apoptosis (Clarke et al, 1993;Lowe et al, 1993b, c), cell cycle arrest (Mcllwrath et al, 1994;Nelson and Kastan, 1994) or drug-induced increases in metastatic potential (McMillan and Hart, 1987). This, together with the evidence for differences in p53 functionality between the cell lines, lead us to postulate that the differences in cell line sensitivity to 5-FU (Figure 2) may be the result of differing cellular responses to drug-induced damage.…”