Chelators as Antineuroblastomas Agents.

Neuroblastoma represents 8-10 % of all malignant tumors in childhood and is responsible for 15 % of cancer deaths in the pediatric population. Aggressive neuroblastomas are often resistant to chemotherapy. Canonically, neuroblastomas can be classified according to the MYCN (N-myc proto-oncogene protein) gene amplification, a common marker of tumor aggressiveness and poor prognosis. It has been found that certain compounds with chelating properties may show anticancer activity, but there is little evidence for the effect of chelators on neuroblastoma. The effect of new chelators characterized by the same functional group, designated as HLZ (1-hydrazino phthalazine), on proliferation (WST-1 and methylene blue assay), cell cycle (flow cytometry), apoptosis (proliferation assay after use of specific pharmacological inhibitors and western blot analysis) and ROS production (fluorometric assay based on dichlorofluorescein diacetate metabolism) was studied in three neuroblastoma cell lines with different levels of MYCN amplification. The molecules were effective only on MYCN-non-amplified cells in which they arrested the cell cycle in the G0/G1 phase. We investigated the mechanism of action and identified the activation of cell signaling that involves protein kinase C.

Small molecule inhibitors of DNA-PK for tumor sensitization to anticancer therapy.

The most sensitive cell structure - a DNA molecule, is the common target of cancer therapy. DNA damage response (controlled by enzymes from the phosphatidylinositol 3-kinase-related kinases family - PIKK) presents many encouraging targets for improving both conventional cytotoxic anticancer therapy and individualized monotherapy. DNA-dependent protein kinase (DNA-PK) is a member of the PIKK superfamily and plays an important role in the detection and repair of DNA double-strand breaks via the non-homologous end-joining pathway. The ability of cancer cells to repair DNA damage is an important element determining their sensitivity to radio- or chemo-therapy. The overactivation of DNA-PK in cancers can result in resistance to anticancer therapy. The inhibition of DNA-PK is a very promising target in anticancer research. However, the specific DNA-PK inhibitors currently known are limited by poor solubility and high metabolic lability in vivo, leading to a short serum half-life. Construction of new compounds based on existing drugs is the most important strategy to improve drug efficacy, pharmacokinetic parameters and to reduce toxicity. This review will describe small molecule inhibitors and summarize their efficacy in synergizing radio- and chemotherapy in vitro.

[Angiotensin converting enzyme inhibitors in controlled hypotension during spinal surgery]. / Inhibitory angiotenzin konvertujícího enzymu v rízené hypotenzi behem spondylochirurgických výkonu.

BACKGROUND: Controlled hypotension is an advantage during spondylosurgical operations: the objective is to achieve a mean arteriae pressure of 8 kPa (60 mm Hg). The most frequently used 0.01% solution of sodium nitroprusside must be increased in some patients to amounts which involve the risk of intoxication. This applies to patients with an increased sympathoadrenal activity and ready mobilization of the renin-angiotensin system. The objective of the present investigation was to test the inhibitor of the angiotensin converting enzyme in hypotension controlled by nitroprusside. METHODS AND RESULTS: To twenty patients before a spondylosurgical operation as premedication angiotensin converting enzyme inhibitor (ACE)--captopril--was administered, 25 mg by the oral route. The control group was formed by 20 patients with spondylosurgery under controlled hypotension with nitroprusside administration. The effect of captopril was manifested by a reduced amount of nitroprusside needed to maintain the median pressure of 8 kPa; in the captopril group 1.073 +/- 0.52 microgram.kg-1.min-1 was used, as compared with 1.786 +/- 1.04 micrograms.min-1 in the control group (p < 0.01). Concurrently monitored values of plasma renin activity were higher in the patients given captopril: 7.352 +/- 5.75 nmol.l-1, as compared with 5.583 +/- 3.73 nmol.l-1 (p < 0.05). CONCLUSIONS: Premedication with ACE inhibitor (captopril), even when administered in small doses via p. o., reduced the sodium nitroprusside consumption by as much as 60%. The elevated plasma renin values were objective evidence of the effect of captopril.

[Initial experience with peroperative autotransfusion in spinal surgery]. / První zkusenosti s peroperacní autotransfúzí ve spondylochirurgii.

The authors describe combinations of anaesthesiological methods which enabled them during extensive spondylosurgical operations in 66 patients to reduce the consumption of homologous blood during operation to 90 ml, on the first day after operation to 300 ml and on the second day after operation to 120 ml. In six patients they used preoperative collection of the patient's own blood, in 45 patients acute normovolaemic haemodilution, in all patients controlled hypotension with sodium nitroprusside to a mean arterial pressure of 8-9 kPa and peroperative collection of blood by means of an autotransfusion apparatus Dideco Stat with a standard programme and yield higher than 50%. During and after peroperative collection they did not record any complications. Lower haemoglobin and haematocrit values and a reduced number of erythrocytes, lower than the lower normal range, during and after operation did not threaten the postoperative course in these patients. The authors draw, however, attention to the rise of the number of leucocytes immediately after operation to 19.7 x 10(9). 1(-1) which is due to their shift into the final product. Solution of this phenomenon which can produce ARDS is according to the authors the use of a programme different from the standard one.