**9. References**


In conclusion, the short biological half-life in the blood and low tumor uptake of the studied radiolabeled pyrido[2,3-*d*]pyrimidines limit the clinical application of these Cdk4/ Cdk6 inhibitors as radiotracers for the characterization of Cdk4/Cdk6 in tumors by means of PET. Nevertheless, further development and evaluation of suitable radiolabeled Cdk inhibitors with optimized properties *in vivo* are still of outstanding interest for the prospective

Critical contribution of cell cycle regulating kinases Cdk to carcinogenesis provides a promising target for diagnostic characterization of malignancies and development of novel therapeutic interventions. Numerous compounds directly inhibiting Cdk and, as a consequence, cell proliferation have been developed, and 9 of them are currently under clinical evaluation (phase I and II) as antitumor agents. Most of the candidates are pan-Cdk inhibitors affecting several Cdk family members with advantages in efficiency of tumor treatment due to not only inhibition of cell proliferation but also apoptosis induction. Only one inhibitor – pyrido[2,3-*d*]pyrimidine PD 0332991 – has been comprehensible described with preferential selectivity for Cdk4 and Cdk6 applicable for Rb positive tumors with primarily defects in Cdk4/ Cdk6 pathway. Application of Cdk inhibitors to patients with advanced cancers resulted in stabilization of disease. Combination with classical chemotherapeutic agents and adjustment of therapeutic schedules may also cause tumor regression and contribute to prevention of drug resistance. More detailed preclinical evaluation using suitable tumor models and focused clinical trials will give valuable implications for new mechanism-based approaches and Cdk drug developments as well as

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**13**

*Belgium* 

**Targeting Tumor Perfusion and Oxygenation** 

*2Pole of Pharmacology (FATH5349), University of Louvain (UCL) Medical School* 

Hypoxia, a partial pressure of oxygen (pO2) below physiological needs, is a limiting factor affecting the efficiency of radiotherapy. Indeed, the reaction of reactive oxygen species (ROS, produced by water radiolysis) with DNA is readily reversible unless oxygen stabilizes the DNA lesion. While normal tissue oxygenation is around 40 mm Hg, both rodent and human tumors possess regions of tissue oxygenation below 10 mm Hg, at which tumor cells become increasingly resistant to radiation damage (radiobiological hypoxia) (Gray, 1953). Because of this so-called "oxygen enhancement effect", the radiation dose required to achieve the same biologic effect is about three times higher in the absence of oxygen than in the presence of normal levels of oxygen (Gray et al., 1953; Horsman & van der Kogel, 2009). Hypoxic tumor cells, which are therefore more resistant to radiotherapy than well oxygenated ones, remain clonogenic and contribute to the therapeutic outcome of

Tumor hypoxia results from the imbalance between oxygen delivery by poorly efficient blood vessels and oxygen consumption by tumor cells with high metabolic activities. On the one hand, oxygen delivery is impaired by structural abnormalities present in the tumor vasculature (Munn, 2003). They include caliber variations with dilated and narrowed single branches of tumor vessels, non-hierarchical vascular networks, disturbed precapillary architecture, and incomplete vascular walls. These structural abnormalities cause numerous functional impairments, i.e. increased transcapillary permeability, increased vascular permeability, interstitial hypertension, and increased flow resistance (Boucher et al., 1996; McDonald & Baluk, 2002). It is however important to note that, although hastily formed immature tumor microvessels lack smooth muscle layer(s) and are therefore unable to provide autoregulation, it is not uncommon to find mature blood vessels with smooth muscle layers and neural junctions inside slow-growing tumors (e.g. most human tumors) (Feron, 2004). On the other hand, the altered tumor cell metabolism with elevated metabolic rates also contributes to the occurrence of hypoxic regions in tumors and further causes extracellular acidification. Tumor hypoxia occurs in two ways: chronic hypoxia (or diffusion-limited hypoxia), and acute hypoxia (or perfusion-limited or fluctuating hypoxia). Chronic hypoxia has classically been thought to result from long diffusion distances

**1. Introduction** 

fractionated radiotherapy (Rojas et al., 1992).

**Modulates Hypoxia and Cancer Sensitivity** 

**to Radiotherapy and Systemic Therapies** 

Bénédicte F. Jordan1 and Pierre Sonveaux2

*1Biomedical Magnetic Resonance Group* 

of the oral multi-CDK inhibitor PHA-848125. *J Clin Oncol,* Vol.26, (May 20 Suppl.), abstract 3531

