Review: potential role of cell cycle synchronizing agents in combination treatment modalities of malignant tumors.

Malignant neoplasms consist of heterogeneous cell populations and their cellular elements proliferate asynchronously. Since the tumor cells of various cell cycle phases respond differently to many chemotherapeutic drugs, attempts at synchronization seemed to be a promising way to achieve a more powerful antineoplastic effect. Mainly based on in vitro data, it was shown that numerous compounds, including hormones, were able to arrest the cell cycle in different phases, and some of them also induced apoptotic cell death. The better understanding of the molecular mechanisms of cell cycle control has brought the cyclin-dependent kinases into focus and hundreds of compounds have been synthesized in order to regulate malignant cells at their checkpoints, especially at G1 progression. Some of these compounds have been found to be effective not only in vitro, but also in in vivo experiments, and they were further evaluated in Phase I - II clinical trials. Generally speaking, these studies have yielded modest, although potentially promising, results, but the adverse effects sometimes restricted the applicability of the products. Nevertheless, extended studies in cancer patients are under way. Moreover, after encouraging preclinical investigations, the combination of cell cycle regulators with different cytostatic drugs may offer a novel therapeutic alternative in the field of oncology.