Clinical relevance of human cancer xenografts as a tool for preclinical assessment: example of in-vivo evaluation of topotecan-based chemotherapy in a panel of human small-cell lung cancer xenografts.

Prediction of human tumor response based on preclinical data could reduce the failure rates of subsequent new anticancer drugs clinical development. Human small-cell lung carcinomas (SCLC) are characterized by high initial sensitivity to chemotherapy but a low median survival time because of drug resistance. The aim of this study was to evaluate the therapeutic relevance of a panel of human SCLC xenografts established in our laboratory using one compromising drug in SCLC, topotecan (TPT).

Cleavage of stalled forks by fission yeast Mus81/Eme1 in absence of DNA replication checkpoint.

During replication arrest, the DNA replication checkpoint plays a crucial role in the stabilization of the replisome at stalled forks, thus preventing the collapse of active forks and the formation of aberrant DNA structures. How this checkpoint acts to preserve the integrity of replication structures at stalled fork is poorly understood. In Schizosaccharomyces pombe, the DNA replication checkpoint kinase Cds1 negatively regulates the structure-specific endonuclease Mus81/Eme1 to preserve genomic integrity when replication is perturbed.

Arrested replication fork processing: interplay between checkpoints and recombination.

The arrest of DNA replication by DNA damage, nucleotide depletion, DNA-protein complexes or following clashes between transcription and replication factors all have the capacity to promote genome instability. In this review, we discuss how DNA replication is regulated by the checkpoint pathways that stabilise arrested replication forks and the recombination factors that process specific DNA structures resulting from fork arrest. We examine what is known about the interplay between the checkpoints and the recombination apparatus and review the evidence for a recombination-based fork restart pathway in eukaryotes.