Current inhibitors of checkpoint kinase 2.

Checkpoint kinase 2 is a serine/threonine protein which functions as an important transducer in apoptosis or DNA repair following activation by DNA damage. Inhibition of checkpoint kinase 2 is thought to sensitize p53-mutated or p53-deficient cancerous cells but protect normal tissue following DNA-damage caused by ionizing radiation or chemotherapeutic agents. The development of checkpoint kinase inhibitors for the treatment of cancer has therefore been a major objective in drug discovery over the past decade. Several inhibitors have been co-crystallized in the active site of checkpoint kinase 2 revealing important features of effective inhibitors. Some of these inhibitors have entered clinical trials in the last decade. This review describes and discusses the most recent inhibitors of checkpoint kinase 2 as reported in the literature, including an evaluation of biological activity.

Preparation of hymenialdisine, analogues and their evaluation as kinase inhibitors.

The natural product hymenialdisine was first isolated in 1980 from the marine sponges of the genera Hymeniacidon, Acanthella, Axinella and Pseudaxinyssa. The structure was elucidated on the basis of X-ray crystallography demonstrating a structurally interesting pyrrole-azepin-8-one ring system bonded to a glycocyamidine ring. Great interest has been taken in synthesizing this type of scaffold due to its potent activity in competitive kinase inhibition. In addition, several patents have claimed pharmacological use of these compounds for prevention and treatment of different diseases. The challenging syntheses of hymenialdisine and its analogues are described in this review as well as their evaluation as kinase inhibitors.

Simultaneous hemodynamic and serological cardiotoxicity monitoring during immunotherapy with trastuzumab.

BACKGROUND: Immunotherapy with trastuzumab (Herceptin), a selective HER-2(ErbB2)-antibody, is associated with a certain degree of cardiotoxicity. This study sought to evaluate the immediate hemodynamic response to trastuzumab with real-time CW-Doppler depending on the level of nt-pro-BNP (brain natriuretic peptide) as a possible marker of cardiotoxicity. METHODS: 48 patients with HER-2-positive metastatic breast cancer were continuously measured with CW-Doppler ultrasound for cardiac output (CO) and systemic vascular resistance (SVR) before, during and after drug infusion in combination with nt-pro-BNP before and 10 min after drug infusion. Depending on the nt-pro-BNP-levels <125 pg/ml (group A, n=34, 51+/-11 years) vs. nt-pro-BNP >125 pg/ml (group B, n=14, 63+/-7 years) two groups have been defined. RESULTS: Trastuzumab therapy did not change nt-pro-BNP immediately before (44+/-29 pg/ml) vs. after the infusion (45+/-32 pg/ml, n.s.) in the low-level as in the high level nt-pro-BNP group (231+/-356 pg/ml prior and 240+/-377 pg/ml, n.s.). Cardiac output remained stable during trastuzumab infusion, however cardiac output was significantly increased following the end of the infusion stronger in the high-level nt-pro-BNP group. Systemic vascular resistance prior to the trastuzumab infusion was higher in the high-level nt-pro-BNP group with significant decrement during and after the infusion. CONCLUSION: Combining real-time CW-Doppler ultrasound and nt-pro-BNP monitoring is feasible to monitor the immediate hemodynamic changes during and after trastuzumab infusion.

Combined NT-pro-BNP and CW-Doppler ultrasound cardiac output monitoring (USCOM) in epirubicin and liposomal doxorubicin therapy.

BACKGROUND: Chemotherapy with epirubicin is approved in women with breast cancer and is associated with a certain degree of cardiotoxicity. HYPOTHESIS: Epirubicin changes stroke volume, cardiac output and systemic vascular resistance, while liposomal doxorubicin does not. METHODS: 75 patients with HER-2-positive metastatic breast cancer were continuously measured with CW-Doppler ultrasound for stroke volume (SV), cardiac output (CO), and systemic vascular resistance (SVR) before, during and after drug infusion in combination with NT-pro-BNP before and 10 min after drug infusion. RESULTS: Epirubicin infusion increased stroke volume significantly in low-level NT-pro-BNP (62+/-23 ml vs. 74+/-29 ml, p=0.004) and high-level NT-pro-BNP (48+/-5 ml vs. 64+/-20 ml, p=0.131), while liposomal doxorubicin infusion increased stroke volume significantly in low-level NT-pro-BNP (54+/-16 ml vs. 67+/-22 ml, p=0.001) and high-level NT-pro-BNP (65+/-22 ml vs. 82+/-27 ml, p=0.001). Cardiac output was significantly increased in epirubicin (p=0.004) by 20% (NT-pro-BNP<125 pg/ml) and not significantly 38% (NT-pro-BNP>125 pg/ml; p=0.144), while in liposomal doxorubicin cardiac output was significantly increased by 23% (NT-pro-BNP<125 pg/ml; p=0.023) and 33% (NT-pro-BNP>125 pg/ml; p=0.001). In liposomal doxorubicin cardiac index was significantly increased by 26% (NT-pro-BNP<125 pg/ml; p=0.021) and 33% (NT-pro-BNP>125 pg/ml; p=0.0001). SVR was significantly reduced during and after epirubicin therapy. CONCLUSION: Using the CW-Doppler USCOM a different hemodynamic response to epirubicin vs. liposomal doxorubicin is evident. Epirubicin leads to a significant upregulation of stroke volume and cardiac output, which is even more pronounced in the high-level NT-pro-BNP group, while liposomal doxorubicin does not change immediate hemodynamics. No deterioration of cardiac function using the real-time CW-Doppler ultrasound USCOM or an increase in NT-pro-BNP levels was evident during epirubicin or liposomal doxorubicin therapy.

["Good advice is precious." The second opinion from the point of view of an interdisciplinary cancer therapy center]. / "Guter Rat ist teuer". Die Zweitmeinung aus Sicht eines interdisziplinären Tumortherapiezentrums.

BACKGROUND AND OBJECTIVE: The setting up of an interdisciplinary tumor treatment center together with a "tumor board" has resulted in early specialty-bridging assessment and therapeutic decisions of cancers, some of them complex, in hospitalized patients with visceral tumors. It was the aim of this study to compare the use and value of the decisions of the tumor board ("second opinion") with those of the original assessment made elsewhere after primary surgical treatment. PATIENTS AND METHODS: Information on the tumor board's database, recorded explicitly as "external comments" or "second opinion" were accessed. The data were then classified according to organs or organ systems and further divided into those cases in which the primary tumor had not been treated, those with tumor recurrence and those with metastases or recurrence of metastases. RESULTS: 8298 cases were evaluated during a five-year period. There were 373 "second opinions" (4.5%), most of the referrals relating to tumors of the upper gastrointestinal tract, corresponding to the focus of our institution. Previously untreated primary tumors amounted to 53.6% of cases, local recurrences in 14.7% and initial evidence of metastases of a visceral tumor in 9.9%. In 21.7% progression of a known metastasizing tumor was the main reason for requesting a second opinion. The second opinion agreed with the external decision for surgery alone in 16.4% of all enquiries. Minor modifications of the external therapeutic decisions were recommended in 5.9% of referred cases, while in 47.2% major changes were recommended. 28,7% of enquiries could not be evaluated because essential data were not available. CONCLUSIONS: Requests for a second opinion in the treatment of visceral tumors are still rare in Germany. Good and current findings are requisites for giving a reliable second opinion. In fewer than a fifth of cases was there agreement with regard to a primarily surgical intervention. The concept of multimodal forms of treatment are usually given priority, which underlines the need for establishing interdisciplinary advisory panels.

FR900482 class of anti-tumor drugs cross-links oncoprotein HMG I/Y to DNA in vivo.

BACKGROUND: Overexpression of the high-mobility group, HMG I/Y, family of chromatin oncoproteins has been implicated as a clinical diagnostic marker for both neoplastic cellular transformation and increased metastatic potential of several human cancers. These minor groove DNA-binding oncoproteins are thus an attractive target for anti-tumor chemotherapy. FR900482 represents a new class of anti-tumor agents that bind to the minor groove of DNA and exhibit greatly reduced host toxicity compared to the structurally related mitomycin C class of anti-tumor drugs. We report covalent cross-linking of DNA to HMG I/Y by FR900482 in vivo which represents the first example of a covalent DNA-drug-protein cross-link with a minor groove-binding oncoprotein and a potential novel mechanism through which these compounds exert their anti-tumor activity. RESULTS: Using a modified chromatin immunoprecipitation procedure, fragments of DNA that have been covalently cross-linked by FR900482 to HMG I/Y proteins in vivo were polymerase chain reaction-amplified, isolated and characterized. The nuclear samples from control cells were devoid of DNA fragments whereas the nuclear samples from cells treated with FR900482 contained DNA fragments which were cross-linked by the drug to the minor groove-binding HMG I/Y proteins in vivo. Additional control experiments established that the drug also cross-linked other non-oncogenic minor groove-binding proteins (HMG-1 and HMG-2) but did not cross-link major groove-binding proteins (Elf-1 and NFkappaB) in vivo. Our results are the first demonstration that FR900482 cross-links a number of minor groove-binding proteins in vivo and suggests that the cross-linking of the HMG I/Y oncoproteins may participate in the mode of efficacy as a chemotherapeutic agent. CONCLUSIONS: We have illustrated that the FR class of anti-tumor antibiotics, represented in this study by FR900482, is able to produce covalent cross-links between the HMG I/Y oncoproteins and DNA in vivo. The ability of this class of compounds to cross-link the HMG I/Y proteins in the minor groove of DNA represents the first demonstration of drug-induced cross-linking of a specific cancer-related protein to DNA in living cells. We have also demonstrated that FR900482 cross-links other minor groove-binding proteins (HMG-1 and HMG-2 in the present study) in vivo; however, since HMG I/Y is the only minor groove-binding oncoprotein presently known, it is possible that these non-histone chromatin proteins are among the important in vivo targets of this family of drugs. These compounds have already been assessed as representing a compelling clinical replacement for mitomycin C due to their greatly reduced host toxicity and superior DNA interstrand cross-linking efficacy. The capacity of FR900482 to cross-link the HMG I/Y oncoprotein with nuclear DNA in vivo potentially represents a significant elucidation of the anti-tumor efficacy of this family of anticancer agents.

Structure-activity relationship for DNA topoisomerase II-induced DNA cleavage by azatoxin analogues.

Eighteen analogues of the nonintercalative DNA topoisomerase II (topo II)-active epipodophyllotoxin-ellipticine hybrid, azatoxin, were synthesized and evaluated for their ability to induce topo II-mediated DNA strand breaks in vitro. In general, the SAR profile of the azatoxins showed more homology with that of the epipodophyllotoxins than with the ellipticines. Of the compounds studied, only fluoro substitution at the 8-, 9, and 10-positions of azatoxins enhanced activity, with 9-fluoroazatoxin being the most active compound in this series.

Inhibition of DNA topoisomerase II by azaelliptitoxins functionalized in the variable substituent domain.

A series of novel C11-substituted derivatives of azaelliptitoxin (azatoxin) have been synthesized and tested for their inhibitory activity against human DNA topoisomerase II. Incorporation of a C11 polyamine or amine resulted in an increase in the intercalation properties of the drug and a decrease of topoisomerase II activity. The structure-activity relationship (SAR) profile of the nonintercalating C11 anilino azatoxin class follows the SAR of the (anilino)acridine family. 11-(4-Cyanoanilino)azatoxin (14) was found to be the most active analog in this series, exhibiting approximately 10-fold higher activity than azatoxin 12 and etoposide.

[Lung function, gas exchange and regulation of ventilation in patients with portocaval encephalopathy (author's transl)]. / Lungenfunktion, Gasaustausch und Atemregulation bei Patienten mit portokavaler Enzephalopathie.

In 17 patients, breathing room air and pure oxygen, with histologically proven cirrhosis of the liver and portocaval encephalopathy grade I, static and dynamic lung volumes, closing capacity and arterial blood gases were determined. Furthermore, CO2, response curves were provided and mouth occlusion pressure measurements were carried out. The residual volume was found to be increased (130 +/- 8% of predicted) which resulted in decreased vital capacity (79 +/- 2% of predicted) with total lung capacity being normal (94 +/- 2% of predicted). Closing capacity was increased to 134 +/- 5% of the predicted value. Gas exchange for oxygen was impaired (AaDO2 = 262 +/- 30% of predicted). Arterial PO2, however, was within normal range PaO2 = 84 +/- 3.6 mm Hg) due to hyperventilation (PaCO2 = 28.1 +/- 0.8 mm Hg). Hypoxic ventilatory stimulation could be excluded because inspiration of pure oxygen caused no change of PaCO2 (PaCO2 = 27.3 + 0.7 mm Hg and PaO2 = 465 + 16.9 mm Hg with FIO2 = 1.0). The slope of the CO2 response curves was normal, the mouth occlusion pressures, however, were higher than the predicted value: up to PaCO2 of 55 mm Hg. The slope of these curves being smaller than predicted. The results show that in patients with portocaval encephalopathy the lung function is disturbed due to premature airway closure with consequently decreased regional ventilation: perfusion ratios and that regulation of ventilation is impaired by a loss of sensitivity for CO2 with high basal output of the respiratory centers not related to CO2.