Early clinical studies exploring new targets in anticancer treatment
Chemotherapy for cancer has always greatly relied upon the use of cytotoxic agents. These agents exert their activity in the process of nuclear DNA and RNA replication, and their activity in sensitive models leads to cell death and subsequent tumor shrinkage. Although a number of human tumor types can nowadays be cured by treatment involving cytotoxic agents, the overall clinical balance of efficacy and toxicity of these agents remains disappointing. In contrast to the situation with cytotoxic agents, where introduction as anticancer agent is usually preceded by large-scale random screening procedures, more recent research has focussed on anticancer agents for which development and design was preceded by the identification of specific tumor-related molecular targets or processes. These targets and processes are located either intracytoplasmic, in the cell membrane, or even completely outside the tumor cell itself. Examples of these molecular targets and processes are the intracytoplasmic polyamine synthesis pathway and farnesyl transferase pathway, the activity of various transmembrane signal transduction pathways, and the enzymatic breakdown of the extracellular matrix and the process of tumor-related angioneogenesis, respectively. Numerous animal studies with these new so-called rationally designed anticancer agents, aiming at one of the above targets, yielded no or only minor toxicity. The predictive value of results of animal studies for the human situation, however, is relatively limited. Nevertheless, in theory, when performing clinical studies with such compounds, toxicity may turn out to be absent or only mild. As a resultant, defining dose limiting toxicity as an endpoint for phase I studies may not be possible, and consequently, defining a recommended dose for additional activity testing might proof to be difficult. Many of these new anticancer agents were shown in preclinical studies to have a cytostatic rather than cytotoxic effect. Although in a limited number of these studies tumor regressions were noted, growth inhibition was the most frequently seen effect. Although, as said, such results cannot easily be extrapolated to the human situation, it may still be anticipated that these agents are not likely to induce tumor regression in clinically detectable tumor masses. Because of this, performing phase II studies might not make too much sense. Taken these considerations together, it is obvious that the design of clinical studies with new cytostatic agents needs a thorough reappraisal. This thesis involves clinical phase I studies performed in this shifting field of anticancer treatment. It outlines several of the problems described above and reports on efforts made to suggest alternative study endpoints.
|Publisher||Erasmus MC: University Medical Center Rotterdam|
|Promotor||Stoter, G. (Gerrit) , Verweij, J. (Jaap)|
|Sponsor||Sheringh-Plough BV, Novartis Pharma BV|
|Keywords||cancer, cancer therapies, chemotherapy, cytostatic agents, neoplasms, oncology|
Eskens, F.A.L.M.. (2001, February 14). Early clinical studies exploring new targets in anticancer treatment. Erasmus MC: University Medical Center Rotterdam. Retrieved from http://hdl.handle.net/1765/22846