Hugues Malonne

DNA topoisomerase targeting drugs: Mechanisms of action and perspectives

The nuclear enzymes DNA topoisomerases I and II appeared as cellular targets for several antitumor drugs: campthotecin derivatives interacting with topoisomerase I, and actinomycin D, anthracycline derivatives, elliptinium acetate, mitoxantrone, epipodophyllotoxine derivatives, amsacrine and a new olivacine derivative, NSC-6596871 (S 16020-2), which interact with topoisomerase II. The functions of these enzymes are numerous and important since they are critical for DNA functions and cell survival. Despite the fact that they share the same target, topoisomerase II inhibitors have different mechanisms of action. Two principle types of induced alterations are involved in cellular resistance to topoisomerase II drugs: qualitative or quantitative alteration of the enzyme and/or increased drug efflux due to overexpression of P-glycoprotein. S 16020-2, a new olivacine derivative with a high antitumor activity against solid tumors, shows a potent cytotoxic effect against tumor cells expressing P-glycoprotein. This observation suggests that the comprehension of the respective effects of topoisomerase inhibitors and the precise knowledge of their mechanisms of resistance would improve the use of this therapeutic class in the clinic within rational chemotherapeutic combinations.

MECHANISMS OF TUMOR ANGIOGENESIS AND THERAPEUTIC IMPLICATIONS : ANGIOGENESIS INHIBITORS

Angiogenesis is the development of new blood vessels from the existing vascular bed. In normal conditions this tightly regulated process occurs only during embryonic development, the female reproductive cycle and wound repair. In contrast, in pathological conditions such as malignant growth, atherosclerosis and diabetic retinopathy, angiogenesis becomes persistent due to an imbalance in the interplay between the positive and negative regulatory signals controlling the process. Thus, the control of tumor neovascularization may lead to new therapeutic approaches. Indeed, several anti-angiogenic drugs are currently undergoing preclinical characterization and/or clinical investigation. Recent achievement has clarified the mechanisms of action leading to pathological angiogenesis and has highlighted the role of hypoxia, growth factors, growth factor-receptors, enzymes and cell adhesion molecules involved in the process. This knowledge has permitted the design of receptor antagonists, adhesion molecule blockers and new targeted vascular approaches including gene therapy.

Long-term tolerability of tramadol LP, a new once-daily formulation, in patients with osteoarthritis or low back pain.

Introduction:  Tramadol hydrochloride is a centrally acting analgesic, which possesses opioid agonist properties and activates monoaminergic spinal inhibition of pain. An oral, once a day, sustained release formulation of tramadol is thought to be advantageous compared with immediate release preparations as it prevents plasma peaks associated with increased side‐effects of the drug. It may also improve compliance. The purpose of the study was to assess the long‐term safety of a new sustained‐release formulation of tramadol (tramadol LP) in patients with knee or hip osteoarthritis and in patients with refractory low back pain.

Characterization of TNP-470-induced modifications to cell functions in HUVEC and cancer cells.

The aim of the present work is to characterize (both in vitro and in vivo) the influence of TNP-470 on different cell functions involved in angiogenesis and, more particularly, on endothelial cell growth, cell migration and vessel formation. In addition, a possible direct anti-tumor activity was investigated. To this end, we made use in vitro of human umbilical cord endothelial vein (HUVEC) cells and two human cancer cell lines. The TNP-470 effects on the growth of cancer cell lines were compared to those of Taxol (an inhibitor of microtubule depolymerization), a cytotoxic reference which also displays strong antiogenic activity at low (non-toxic) doses. The in vitro effects were characterized on the mouse mammary MXT adenocarcinoma, on which we also characterized the influence of three clinically active anti-tumor compounds (as cytotoxic references). The purpose of this part of the study was to determine the actual TNP-470-related anti-tumor activity and to evaluate the possible toxic side-effects at the doses at which this compound induces tumor growth inhibition. These investigations were completed by analyzing the TNP-470 effects on HUVEC cell motility and in vitro and in vivo vessel formation. The results show that in vitro, TNP-470 inhibited the growth not only of HUVEC, but also of neoplastic cells. Furthermore, TNP-470 clearly inhibited in vitro endothelial cell motility (p<10(-5)). However, it had only a minor effect (p=0.02) on the formation of HUVEC cell networks on Matrigel(R). In vivo, TNP-470 was able to inhibit tumor growth (on the MXT model) at a dose (50 mg/kg) associated with toxic side-effects. Histological examination showed a significant inhibition of vessel formation (p<0.001) at high (toxic) and intermediary (non-toxic) doses (50 and 20 mg/kg). However, we also observed that TNP-470 stimulated lymphocyte proliferation. Thus, care must be taken with the TNP-470 compound in combination with other anti-tumoral agents in order to avoid certain unfortunate clinical complications.

Differences in efficacy found in animals between recombinant forms of erythropoietin will not necessarily translate into differences in humans

doi:10.1038/sj.bjc.6600503 www.bjcancer.com