Apoptosis-modulating agents in combination with radiotherapy-current status and outlook

To increase the therapeutic efficacy of ionizing radiation or to reduce radiation-mediated side effects, diverse research centers for translational radiation oncology have headed for a specific modulation of defined cellular death pathways. In this regard, several signaling systems have proved to be of high potential value.

It has previously been shown that apoptotic pathways induced by ionizing radiation are distinct from death pathways triggered by death ligands such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The combination of both radiation and TRAIL was highly efficient in vitro and in preclinical mouse models. However, several aspects of normal tissue toxicity have not been solved, and no Phase I data are available yet. A second approach tested in a Phase I trial is based on the observation that synthetic phospholipid derivatives (alkyllysophospholipids and alkylphosphocholines) strongly enhance apoptotic effects by modulating the balance among the mitogenic, anti-apoptotic MAPK, phosphatidylinositol 3'-kinase (PI3K)/Akt, and the pro-apoptotic SAPK/JNK signaling pathways. Furthermore, others have provided evidence that inhibition of anti-apoptotic signals generated by mitogenic stimuli may increase radiation responses. In this context, controversial data are available regarding the influence of a pharmacologic abrogation of MEK1, Erk1/2 signaling on apoptotic sensitivity but no Phase I trials of MEK inhibitors either alone or in combination with radiation have yet been published. However, inhibition of the PI3K/Akt survival pathway using compounds such as the protein kinase C (PKC) inhibitor PKC412 has been shown to induce apoptosis or to increase the apoptotic sensitivity of tumor cells. Therefore, these drugs may be used alone or in combination with radiation to increase tumor control; however, Phase I data are lacking. Several other drugs, including cyclooxygenase-2 inhibitors, betulinic acid, and proteasome inhibitors, have been shown to interact with apoptotic signal transduction. Again, most of the drugs have not been tested in combination with radiation in vivo or-in the case of cyclooxygenase-2 inhibitors-exert pleiotropic effects.

Although the examples do not reflect all available strategies, it is clear that several promising approaches targeting defined cell death pathways have been developed and entered into clinical trials. The use of synthetic phospholipid derivatives in a Phase I trial is an important example, proving that basic research in radiation biology finally guides the development of new treatment strategies. This, and other approaches, will hopefully increase tumor control rates and reduce side effects in the future.