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BACKGROUND: Companion animals like dogs frequently develop tumors with age and similarly to human malignancies, display interpatient tumoral heterogeneity. Tumors are frequently characterized with regard to their mutation spectra, changes in gene expression or protein levels. Among others, these changes affect proteins involved in the DNA damage response (DDR), which served as a basis for the development of numerous clinically relevant cancer therapies. Even though the effects of different DNA damaging agents, as well as DDR kinetics, have been well characterized in mammalian cells in vitro, very little is so far known about the kinetics of DDR in tumor and normal tissues in vivo. DISCUSSION: Due to (i) the similarities between human and canine genomes, (ii) the course of spontaneous tumor development, as well as (iii) common exposure to environmental agents, canine tumors are potentially an excellent model to study DDR in vivo. This is further supported by the fact that dogs show approximately the same rate of tumor development with age as humans. Though similarities between human and dog osteosarcoma, as well as mammary tumors have been well established, only few studies using canine tumor samples addressed the importance of affected DDR pathways in tumor progression, thus leaving many questions unanswered. SUMMARY: Studies in humans showed that misregulated DDR pathways play an important role during tumor development, as well as in treatment response. Since dogs are proposed to be a good tumor model in many aspects of cancer research, we herein critically investigate the current knowledge of canine DDR and discuss (i) its future potential for studies on the in vivo level, as well as (ii) its possible translation to veterinary and human medicine.

Combined radiochemotherapy treatment modalities are in use for many indications and there-fore of high interest. Even though a combined modality in clinical use is often driven by prag-matic aspects, mechanistic preclinical-based concepts of interaction are of importance in order to translate and implement an optimal combination and scheduling of two modalities into the clinics. The use of microtubule stabilizing agents is a promising strategy for anti-cancer therapy as a part of combined treatment modality with ionizing radiation. Traditionally, microtubule targeting agents are classified as cytotoxic chemotherapeutics and are mostly used in a maxi-mally tolerated dose regimen. Apart from direct cytotoxicity and similar to mechanisms of mo-lecular targeting agents, microtubule stabilizing agents interfere with multiple cellular process-es, which can be exploited as part of combined treatment modalities. Recent preclinical investi-gations on the combination of ionizing radiation and microtubule stabilizing agents reveal new mechanistic interactions on the cellular and tumor level and elucidate the supra-additive tumor response observed particularly in vivo. The major focus on the mechanism of interaction was primarily based on radiosensitization due to cell cycle arrest in the most radiosensitive G2/M-phase of the cell cycle. However, other mechanisms of interaction such as reoxygenation and direct as well as indirect endothelial damage have also been identified. In this review we sum-marize and allocate additive and synergistic effects induced by the combined treatment of clini-cally relevant microtubule stabilizing agents and ionizing radiation along a described radiobio-logical framework encompassing distinct mechanisms relevant for exploiting the combination of drugs and ionizing radiation.

Human DNA polymerase (pol) λ functions in base excision repair and non-homologous end joining. We have previously shown that DNA pol λ is involved in accurate bypass of the two frequent oxidative lesions, 7,8-dihydro-8-oxoguanine and 1,2-dihydro-2-oxoadenine during the S phase. However, nothing is known so far about the relationship of DNA pol λ with the S phase DNA damage response checkpoint. Here, we show that a knockdown of DNA pol λ, but not of its close homologue DNA pol β, results in replication fork stress and activates the S phase checkpoint, slowing S phase progression in different human cancer cell lines. We furthermore show that DNA pol λ protects cells from oxidative DNA damage and also functions in rescuing stalled replication forks. Its absence becomes lethal for a cell when a functional checkpoint is missing, suggesting a DNA synthesis deficiency. Our results provide the first evidence, to our knowledge, that DNA pol λ is required for cell cycle progression and is functionally connected to the S phase DNA damage response machinery in cancer cells