The Cancer Journal - Volume 8, Number 6 (November-December 1995)
Antitumour chemotherapy, new mechanisms of chemoresistance, and played out ideas
In their review on new mechanisms of resistance to anticancer (antitumour) chemotherapy, Singh et al. describe a body of knowledge on this important clinical issue and also outline the advances in the molecular and cellular approach used by biological research to overcome the failings of medicine. Whether this is the right approach is a moot point considering the objective and stakes in hand.
Antitumour chemotherapy took its cue from the concepts born from antibacterial chemotherapy after a lapse of some twenty years. These concepts were target heterogeneity, emergence of resistant variants, and ability to kill these variants by the association of several, supposedly complementary, agents.
However, these two types of therapy differ : effective antibiotics are far more varied than are antitumour agents; the potential for innovation is greater; resistance to antibiotics is a permanent and continuous process within the bacterial world. On the other hand, the process experienced by each new patient with cancer is one that runs right through from its origin to the possible expression of chemoresistance, even though de novo resistance is frequent. The greatest caution should therefore be exercised in the choice of concepts and hypotheses.
There are two practical aims to the cellular and molecular analysis of tumour resistance to chemotherapy :
1. To identify the mechanisms that can be acted upon pharmacologically to restore the efficacy of chemotherapy; to prevent chemoresistance either by (i) inventing novel agents that induce tumour regression without selecting resistant variants or increasing their number by iatrogenic mutation, or by (ii) adding to antitumour agents drugs that have no intrinsic antitumour potency but that are able to interfere with their action and foil the mechanisms of resistance.
2. To invent a reliable method of identifying, prior to chemotherapy, the biological signs of chemoresistance in tumour cell populations. This would establish the contraindications to the use of cytotoxic agents especially for those cancers that are rarely sensitive to such agents. The widespread practice of administering chemotherapy to all patients can no longer be tolerated considering the low expected benefit/side-effects ratio. Patients, their families, as well as medical teams are eager for a clinical revolution that is, however, for ever postponed because chemotherapeutic activism still has a strong hold on mentalities.
The second of these two aims needs to be clearly formulated by the clinicians and discussed by the biologists. It is time to redefine the priorities of cancer research and to stop endlessly repeating the same projects which, protocol after protocol, so often lead to the failure that could have been forecast right from the start. The fact that a clinical trial is international, randomized, approved by an ethics committee, methodologically faultless, expensive, and energy consuming - as regards hardships endured and broken hopes - does not necessarily mean that it is legitimate.
The potential of our ever-increasing knowledge of tumour biology is not fully exploited. The basis for the formulation of our clinical/biological ideas is too narrow. Whether we are dealing with resistance to chemo- or radiotherapy, with manipulation of the immune system or of growth and differentiation factors, we have too good a hand for us to continue playing a routine card game. On the subject of therapeutic and research strategies, we shall soon open up a discussion forum on the Internet (http://www. Infobiogen.fr/journals) from which only played out ideas will be banned.