[Principles of modern oncologic surgery]. / Chirurgische und interdisziplinäre Behandlungskonzepte in der modernen Onkologie.

Principles of modern oncologic surgery Abstract. A substantial proportion of patients seeking surgery suffer from malignant tumors, leading to big challenges for surgeons. The diversity of oncological disease patterns has become more complex in recent years, partly due to advances in molecular pathological diagnostics. As a result, a simple and universally valid treatment concept is not possible. Interdisciplinary therapy must concentrate on identifying and localizing the primary tumor, treating each case individually in accordance with its stage. By the same token, the fundamental objective of a complete resection of the tumor together with its lymph nodes must be pursued in order to reach a high cure rate. Surgical therapy is still an indispensable part of modern oncological treatment - despite rapid progress in conservative oncology. In the last decade a trend towards laparoscopic surgery, partially even in robotic assisted procedures, has evolved. Thus perioperative morbidity and mortality have been reduced due to less invasive surgical techniques. Even at an advanced stage of cancer with metastases a therapy approach involving surgery with curative intention has been established for many types of malignant tumors. At the beginning of any treatment, the therapy concept must be planned within the framework of an interdisciplinary tumor conference. Likewise in palliative oncology, surgery is of importance. This is particularly the case with inaccessible gastrointestinal tumors. By employing bypass procedures, quality of life can be improved considerably, when every other therapy option has been exhausted. The following article aims to offer an overview of the principles of oncological surgery.

Optimized anti-tumor effects of anthracyclines plus Vinca alkaloids using a novel, mechanism-based application schedule.

Application of anthracyclines and Vinca alkaloids on the same day represents a hallmark of polychemotherapy protocols for hematopoietic malignancies. Here we show, for the first time, that both drugs might act most efficiently if they are applied on different days. Proof-of-concept studies in 18 cell lines revealed that anthracyclines inhibited cell death by Vinca alkaloids in 83% of cell lines. Importantly, in a preclinical mouse model, doxorubicin reduced the anti-tumor effect of vincristine. Both drugs acted in a sequence-dependent manner and the strongest anti-tumor effect was obtained if both drugs were applied on different days. Most notably for clinical relevance, in 34% of 35 fresh primary childhood leukemia cells tested in vitro, doxorubicin reduced the anti-tumor effect of vincristine. As underlying mechanism, doxorubicin activated p53, p53 induced cell-cycle arrest, and cell-cycle arrest disabled inactivation of antiapoptotic Bcl-2 family members by vincristine; therefore, vincristine was unable to activate downstream apoptosis signaling. As molecular proof, antagonism was rescued by knockdown of p53, whereas knockdown of cyclin A inhibited vincristine-induced apoptosis. Our data suggest evaluating anthracyclines and Vinca alkaloids on different days in future trials. Selecting drug combinations based on mechanistic understanding represents a novel conceptional strategy for potent polychemotherapy protocols.

Activation of DNA damage response by antitumor therapy counteracts the activity of vinca alkaloids.

BACKGROUND/AIM: Anthracyclines have been proven able to reduce the activity of vinca alkaloids by induction of cell-cycle arrest. The present study aims at identifying the critical initiation steps of signal transduction which transduce the inhibitory effects on the cytotoxicity of vinca alkaloids. MATERIALS AND METHODS: Several new cytostatic drug classes were evaluated together with vincristine in tumor cell lines and patients' tumor cells. RNA interference was used for molecular analyses. RESULTS: Inhibition of vincristine was observed by all cytostatic drugs, which induced cell-cycle arrest. Knockdown of proteins of the DNA damage response ascribed the inhibitory effect to a common pathway involving Chk-1, p53 and p21. Upstream of Chk-1 signal transduction depended on both ATM and ATR for all drugs except methotrexate. CONCLUSION: We have identified critical signaling steps of the DNA damage response system activated by cytostatic drugs, which reduce the anti-tumor activity of vinca alkaloids. The obtained results encourage the development of novel therapeutic strategies to prevent pathway interactions based on the molecular understanding of drug action and drug-drug interactions.