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BACKGROUND/AIM The aim of the study was to investigate the dosimetric characteristics of electron beams with a tungsten functional paper (TFP) surface collimator. MATERIALS AND METHODS The circular field of 6.0 cm diameter was created with the TFP collimator put on the phantom. Depth and lateral dose profiles for 4 and 6 MeV electron beams were obtained. The characteristics of lateral dose profile, treatment diameter as width over 90% of the dose, and penumbra as width of the off-axis positions from 80% to 20% dose levels were evaluated. RESULTS Compared to the lead collimator, the TFP collimator generated higher surface doses, the treatment diameters were increased from 42.8 to 48.6 mm and from 40.0 to 41.4 mm, and the penumbras were reduced from 15.0 to 9.6 mm and from 16.4 to 13.0 mm for 4 and 6 MeV electron beams, respectively. CONCLUSION The TFP surface collimator can provide an excellent dose distribution compared to the conventional lead collimator.

Tumor interstitial fluid (TIF), a component of the tumor microenvironment, is a valuable source of molecules and substances that help in diagnosis and prognosis of solid tumors. There is still no consensus on the optimal method for collecting TIF. Therefore, this study aimed to evaluate the effectiveness of a new method of collecting TIF in invasive ductal carcinoma (IDC) samples for cytokine interleukin 1β (IL1β) quantification.Forty women allowed the collection of TIF using absorbent paper strips during the performance of the core biopsy. The samples were stored at a temperature of -80°C and then analyzed using an enzyme-linked immunoassay.The mean values for IL1β and total protein were 11.39 mg/ml and 2.15 mg/ml, respectively.it was possible to quantify the cytokine IL1β and the total protein concentration present in the tumor tissue through TIF collection with the use of absorbent paper filters, demonstrating the effectiveness of this new method in oncology.

BACKGROUND/AIM: Chimeric antigen receptor (CAR) T cells with tumor specificity are being increasingly investigated. Phase I trials are the first step of testing for safety of novel CAR-T therapy to determine the maximum tolerated dose (MTD). Several dose escalation methods have been developed over time including rule-based, model-based and model-assisted designs. The goal of this project is to overview the phase I designs used in current CAR-T trials. MATERIALS AND METHODS: We searched PubMed for peer-reviewed literature published between January 1, 2015 and December 31, 2021. The search was limited to human studies in the English language using the keywords “CAR-T phase I”, “clinical trials”, and “full text”. RESULTS: One hundred nine papers with at least partial phase I components were included for analysis. 31.2% of the trials used the traditional 3+3 or a variation of said design, and 60.6% did not mention the dose escalation design. The majority of the manuscripts (59.6%) did not report cohort size while 19.3% did not specify the timing of evaluation. Although most of the studies were registered with CT.gov, only 33.9% had any results submitted or posted to CT.gov. These trends persisted even in manuscripts published in journals with high impact factors. CONCLUSION: Standardizing the publication criteria and providing basic elements of phase I clinical trials are critical to ensure high quality of manuscripts. With the quick development and high costs of CAR-T cell therapy, adoption of advanced designs such as model-based and model-assisted should increase to improve efficiency of clinical trials.

Background/aim Electrochemotherapy (ECT) is a predominately palliative treatment for cutaneous metastases where an electric field is used to increase the intracellular accumulation of a chemotherapeutic drug (bleomycin or cisplatin). ECT induces a strong anti-vascular effect and endothelial cells seem especially vulnerable. To date, almost no neurological and/or cerebrovascular complications after ECT treatment have been published. In this paper two such cases are reported. Case report A seizure in a man treated with ECT for a basal cell carcinoma in the temporal region and a fatal ischemic stroke in a woman treated for cutaneous metastases in the neck are reported. In both cases a causal relationship to ECT treatment was strongly suspected. Conclusion ECT in the head and neck can potentially cause severe neurological complications. Ultrasound is recommended for ECT treatment in the neck.

CD58 is an immune adhesion molecule on the cellular surface. It was previously found that a high expression of CD58 predicted a poor prognosis of patients with lower-grade gliomas. Therefore, the aim of this paper was to investigate the association between CD58 and breast cancer.CD58 gene expression data downloaded from cBioPortal was compared between the different subtypes of breast cancer. Clinical prognosis was examined using Kaplan-Meier analysis and multivariable Cox regression analysis. The association between CD58 expression and immune cell infiltration was estimated using the TIMER 2.0 web platform. Finally, the tumour sphere formation of aldehyde dehydrogenase 1 (ALDH1)CD58 mRNA was mainly enriched in claudin-low and basal-like subtypes. The high expression of CD58 predicted a good prognosis in patients with luminal A and luminal B breast cancer. This prediction may be due to the association of immune cell infiltration with CD58. Notably, patients with luminal A breast cancer with a high expression of CD58 in association with ALDH1A3 exhibited a good prognosis; however, this did not apply to patients with basal-like breast cancer. The in vitro experiments revealed that knockdown of CD58 inhibited the tumour sphere formation ability of ALDH1CD58 may function as a potential prognostic biomarker and therapeutic target in ALDH-positive basal-like cancer stem cells.

Background/aim Jellyfish collagen serves as a competitive alternative to mammalian-sourced collagen in many practical aspects. For instance, jellyfish collagen lacks religious constraints when compared to bovine or porcine sources and promises batch-to-batch consistency. Another advantage is its structural similarity with many mammalian collagen types, providing a biocompatible matrix for different cell types as "collagen type 0". This paper intends to investigate jellyfish collagen (Jellagen®) in two applications. This investigation aims to establish an initial understanding of jellyfish collagen in biotechnology. More specifically, in cell culture and the field of tissue engineering. Materials and methods The jellyfish collagen was comparatively tested as a coating material for multi-well plates as one of the most extensively used tools in cell culture and in the form of three-dimensional (3D) scaffolds intended for bone tissue engineering (BTE) applications. Both, the coated well plates and the scaffolds were seeded with fibroblasts and pre-osteoblasts, separately. In vitro cytocompatibility assays in accordance with EN ISO 10993-5/-12 regulations and LIVE-DEAD-stainings were carried out to study the cell viability, cytotoxicity and proliferation of these two cell lines. Results The results showed that collagen extracted from R. pulmo jellyfish can be an alternative to mammalian-derived collagen. Fibroblasts showed comparable cell viability to the medium control and an increased cell proliferation on the well plates indicating that these coated well plates can be used in cell culture, particularly in biocompatibility studies of biomaterials (as fibroblasts are used in this respective field extensively). The viability of pre-osteoblasts significantly exceeded the medium control in case of the jellyfish 3D scaffolds. Conclusion These cells exhibited favorable healthy behavior on this marine collagen, suggesting that Jellagen® collagen can be used in studies of (bone) tissue regeneration and especially as scaffolds in BTE. In conclusion, jellyfish collagen provides biocompatibility and adhesive properties for both cell culture and BTE applications.

Purpose: This paper reports a prospective study designed to measure the accuracy of mammography, ultrasonography, fine needle aspiration cytology and one of the most recently introduced techniques, vacuum biopsy, in the diagnosis of breast cancer. Experimental Design: A sample of 146 breast lesions on 135 patients were examined at our Breast Centre. The lesions had been examined previously at different outpatient centres, without any definite conclusion being reached. The design of the study made it possible to compare MRx, US, FNAC and VB directly, because it excluded several confounding variables. The histological diagnosis on surgical specimen, when available (45 cases), was considered as the gold standard. In the other 101 cases the biopsy results complemented by the negative clinical results of the follow-up were taken to be the true outcome. Statistical indicators (sensitivity, specificity, predictive values PPV and NPV, FN and FP rates, suspicious plus indeterminate rate and likelihood ratios) have been calculated. Results: The NPV of MRx and US are remarkably high (92.4% and 97.9% respectively), confirming previous reports. Complete sensitivity of FNAC turns out to be 80%, while specificity and LR of positive test were 99.1% and 88.8 %. The combined score of FNAC, US and MRx results in a good increase in complete sensitivity (97.1%), if compared with the results of the single diagnostic tests evaluated separately. Absolute sensitivity of VB is 97.1% and specificity is 100%. Conclusions: Considered together, MRx, Us and FNAC appear to be reliable diagnostic procedures and when they are all negative the possibility of a cancer is extremely low (NPV = 0.988 in our sample of women) although it cannot be completely ruled out. The VB test, obviously, has the highest absolute sensitivity among all methods compared and is significantly more sensitive than the Combined Score. Therefore, this technique could be considered conclusive in diagnostic doubtful cases, avoiding open surgical biopsy. 1. Introduction Breast cancer accounts for one-third of cancer diagnoses (more than 192,200 new cancer cases in 2001) and 15% of cancer deaths in U.S. women1,2 and is believed to be the most common cause of malignancy for women in most other Western countries too. In Europe breast cancer accounts for 34% of all prevalent cancers in females and in Italy over 33000 new breast cancer cases are expected in 20023. Over the last 25 years the diagnostic approaches and therapeutic strategies for breast cancer have changed dramatically and mortality rates have fallen by 21% as a result of earlier detection and improved treatment. The diagnostic tools have gradually become more diversified and sophisticated, with a consequent improvement in their resolution limits and accuracy, the tools referred to being digital mammography, ultrasound (US associated with Colour Doppler, Power Doppler, Contrast Agents), magnetic resonance, fine needle aspiration biopsy (FNAC), Core Biopsy (CB), Vacuum Biopsy (VB) and advanced breast biopsy instrument (ABBI). A crucial role has been played by the introduction of national screening programmes4. At present, according to the European Quality Assurance Guidelines in Mammography screening5 the “Triple Approach” is recommended: combined physical examination, mammography (MRx) and FNAC. By introducing mammography screening programmes, however, the size of detected breast lesions has become smaller and the diagnostic problems greater6 so that it seems necessary to redefine the conditions and indications in the use of the new diagnostic tools recently developed. The aim of this paper is to describe a prospective study carried out in a well defined clinical and experimental setting in order to report the accuracy of certain well-established techniques, such as MRx, US and FNAC in our sample of women, and to measure the accuracy of a recently introduced one, VB, in the diagnosis of breast cancer.

Thyroid cancer (TC) is a common malignancy of the endocrine system. The global incidence of TC has increased dramatically in recent years. The available tumor biomarkers are not specific to TC and therefore finding new markers which could be helpful in the diagnostic process, prognosis and treatment of TC patients is a great challenge facing present and future researchers. Chemokines are small chemotactic proteins which play a significant role in the migration of leukocytes to many sites of the inflammatory process. It has been suggested that these molecules are able to promote cancer development by mediating inflammation. This paper presents the general structure of chemokines and their receptors as well as their potential significance in TC. The final aspect of this review is a summary of current knowledge and research results concerning the potential significance of selected chemokines and their specific receptors as candidates for novel tumor markers of TC.

The genetic factors involved in the multistep process of carcinogenesis can be divided at least into two major categories: 1. Mutated or lost genes, which may directly represent one step in the sequential process (tumour suppressor genes); inheritance of one tumour suppressor gene causes dominant expression of the carcinogenic phenotype (the dominant inheritance is described in the accompanying paper); 2. Other genes, which lead to conditions that favour the development of cancer and generally are inherited in a recessive fashion; they are the subject of this paper. Autosomal recessively inherited diseases, such as xeroderma pigmentosum, ataxia-telangiectasia, Bloom's syndrome and Fanconi's anaemia display increased genome instability (chromosomal fragility and/or DNA-repair deficiencies) and are associated in the homozygote and probably also in the heterozygote state with defined malignancies. Neoplasms particularly of the lymphoreticular system frequently occur in patients with genetically determined immunodeficiencies (e.g. severe combined immune deficiency or Wiskott-Aldrich syndrome). People differ due to their individual genetic constitution in their responses to various classes of carcinogens such as physical and chemical agents, to dietary habits, as well as to viruses. Furthermore, tumours are often found in patients displaying premature aging (e.g. Werner's syndrome). In addition, several metabolic abnormalities such as genetic syndromes featuring chronic liver disease, but also many other inherited metabolic conditions have cancer as a regular or frequent complication.

Zyxin (ZYX) is a LIM domain protein whose presence has been detected in the cytoplasm and nucleus. ZYX can translocate between these two compartments and therefore, can take part in the regulation of various cellular processes. VASP and α-actinin are examples of proteins that interact with ZYX. As ZYX is present in focal adhesions (FAs), an immense part of research is focused on the role of this protein in the organisation and function of the cytoskeleton. Other studies aim to explain the impact of zyxin on other intracellular processes. Zyxin has been shown to take part in apoptosis, as well as in wound healing. Additionally, zyxin contribution to cancer development is gaining growing interest. This paper aims to systematise the knowledge on zyxin and its role in carcinogenesis.

Background/Aim: Medullary thyroid cancer (MTC) is highly malignant, metastatic and recurrent, remaining generally incurable, and responsible for approximately 14% of all thyroid carcinoma-related deaths. MTC can metastasize to lymph nodes, trachea and distant organs, such as brain, lungs, liver and bones. MTC cells are resistant to chemotherapy and traditional external therapies are not showing definite clinical benefits. Scientists are trying to understand the molecular background of carcinogenesis and histone deacetylase (HDAC) seems to play a potential role to gene transcription. On the other hand, HDAC inhibitors (HDACI) hamper the HDAC action giving promising results as new anticancer drugs. The purpose of this review was to evaluate the current status of research considering the role of HDACIs in MTC treatment and to present the latest trends in MTC treatment protocols. Materials and Methods: This literature review was accomplished using the MEDLINE database. The key words/phrases were; HDACI, medullary thyroid cancer, HDACI in the therapy of neuroendocrine tumors, HDACI in MTC. Forty-one articles were selected from the total number of the search's results. Only sixteen papers focus on the use of HDACIs in the treatment of MTC. In order to extract our conclusions, we took into account some studies whose main topic does not strictly refer to the MTC but they contain noteworthy and useful information. Only English articles published up to August 2016 were assessed and used for writing this review. Results: Molecules, such as valproid acid (VPA), vorinostat, suberoyl bis-hydroxamic acid (SBHA), depsipeptide, belinostat, m-carboxycinnamic acid bis-hydroxamine (CBHA) and AB3 have shown promising antitumor effects against MTC. Conclusion: HDACIs represent a promising field for targeted therapy both for its anticancer properties, as well as for augmenting radiotherapeutic modalities. More trials are needed.

The aim of the present study paper was to identify the role of reactive oxygen species (ROS) in apoptosis signaling mechanisms. We used for this purpose two ruthenium complex compounds based on that overproduce these reactive species by their metabolism thus manifesting their antitumor activity too.In vivo studies were performed in Walker 256 carcinoma-bearing Wistar rats treated with two ruthenium (III) (Ru(III)) complexes with -fluoroquinolones norfloxacin and ofloxacin. The treatment started 7 days after tumor grafting. We assayed the dynamics of apoptosis by flow-cytometry and the biochemical oxidative status parameters. The biological samples used were serum and whole-tumor tissues; the results were compared to the untreated control group.The results showed an increase of apoptosis from 14.79% to 59.72% 14.79% to 59.72% in tumor cells treated with the most active combination, ruthenium complex with norfloxacin. We also noted an increase of the oxidative status and ROS production during treatment.The newly-synthesized complexes are less toxic and their activity is based on the induction of oxidative stress.

Breast cancer is the most frequent malignancy in females. Due to its major impact on population, this disease represents a critical public health problem that requires further research at the molecular level in order to define its prognosis and specific treatment. Basic research is required to accomplish this task and this involves cell lines as they can be widely used in many aspects of laboratory research and, particularly, as in vitro models in cancer research. MCF-7 is a commonly used breast cancer cell line, that has been promoted for more than 40 years by multiple research groups but its characteristics have never been gathered in a consistent review article. The current paper provides a broad description of the MCF-7 cell line, including the molecular profile, proliferation, migration, invasion, spheroid formation, its involvement in angiogenesis and lymphangiogenesis and its interaction with the mesenchymal stem cells.

This paper focuses on the influence of chemoresistance on the herpes simplex virus (HSVtk)/ganciclovir (GCV)-induced bystander effect (BE), as studied in a human small cell lung cancer (SCLC) cell line (GLC(4)) and its sublines with in vitro acquired resistance to adriamycin (GLC(4)/ADR), mitoxantrone (GLC(4)/MITO) and cisplatin (GLC(4)/CDDP). Chemoresistance for adriamycin, mitoxantrone and cisplatin significantly changed GCV sensitivity. A significant BE was found in all GLC(4) cell lines. Compared to the parental GLC(4) cell line, the BE was significantly higher only for the GLC(4)/ADR cell line. No expression of the nucleoside transporters MRP4 and MRP5 was detected. In all cell lines expression of connexin 43 was found, but modulation of gap junctional intercellular communication (GJIC) by 18-a-glycyrrhetinic acid did not significantly change the BE in any of the GLC(4) cell lines. In conclusion, chemoresistance can influence the HSV-tk/GCV-induced BE, which seems not to be related to differences in MRP4/MRP5 expression or to differences in GJIC.

Synchronous primary gastric adenocarcinoma and lymphoma is a rare occurrence. The aim of the present retrospective study was to analyze the clinicopathological characteristics and therapeutic outcomes of patients with this rare condition to identify post-therapeutic prognostic factors.A PubMed and MEDLINE search was performed to identify relevant articles, using the keywords 'gastric cancer' and 'gastric malignant lymphoma', while additional articles were obtained from references within these papers. A total of 57 patients who were treated for synchronous primary gastric adenocarcinoma and lymphoma were included in the study. A retrospective review was performed on the clinical characteristics of this disease.The median survival time for patients in this study was 81 months and the overall 1- and 5-year survival rates after therapy were 77.6% and 69.0%, respectively. The median survival period of patients with an advanced gastric cancer was significantly shorter than for early gastric cancer (p0.001), while the depth of gastric lymphoma invasion did not significantly affect survival time. The median survival period of patients who underwent total gastrectomy was significantly shorter than that of those who underwent distal gastrectomy (p=0.035). Gastric lymphomas were significantly larger than the gastric adenocarcinomas (6.0 vs. 2.7 cm, respectively; p=0.012).The prognosis for synchronous gastric adenocarcinoma and lymphoma might depend more on the behavior of the adenocarcinoma than on the lymphoma, in which case the treatment and therapeutic outcomes could depend on the adenocarcinoma status.

In this paper we report EPR studies on the effects of meta-Iodobenzylguanidine (MIBG), a structural analogue of norepinephrine capable of inhibiting complex I and III of the respiratory chain, on the reduction state of the various complexes of the respiratory chain in beef heart submitochondrial particles. The EPR spectrum of SMPs incubated with MIBG showed completely reduced prosthetic groups of complex I, but oxidised prosthetic groups of complex IV. This indicates that complex I is inhibited by MIBG at the end of the complex (i.e. at the Q binding site). Determination of the exact site of inhibition of MIBG on complex III yielded no conclusive results, but did confirm that complex III is indeed inhibited by MIBG

In this paper we report the effects of the combination of MIBG (a structural analogue of norepinephrine, used in its radio iodinated form for the diagnosis and therapy of neuroblastoma) and hyperbaric oxygen on the human neuroblastoma cell line SK-N-BE(2c). Exposure of the neuroblastoma cells to hyperbaric oxygen conditions enhanced the effects of MIBG on cell proliferation, lipid peroxidation and energy metabolism of the cell line. Cell proliferation and energy metabolism were further decreased and lipid peroxidation further increased. Enhancement of the effects of MIBG by HBO may provide an explanation for the positive effects on the cumulative survival curve observed when stage IV neuroblastoma patients were treated with the combination of [131I] MIBG and HBO

Accumulating experimental and clinical evidence has indicated that tumor-initiating or cancer stem-like cells are a sub-population of tumor cells capable of initiating and driving tumor growth, and cancer stem-like cells are resistant to most current cancer therapies, including chemo- and radiation therapy. More effective targeted-therapeutic approaches are urgently needed to eliminate cancer stem-like cells. Here, we report that broussoflavonol B, a chemical purified from the bark of the Paper Mulberry tree (broussonetia papyrifera), exhibited potent growth inhibitory activity towards estrogen receptor (ER)-negative breast cancer SK-BR-3 cells at sub-micromolar concentrations. Broussoflavonol B more potently inhibited growth and induced differentiation of stem-like SK-BR-3 cells-compared to the anti-estrogen tamoxifen. In addition, broussoflavonol B treatment also reduced the steady, state levels of the Human epidermal growth factor receptor-2 (HER2) and ER-α36, a variant of ER-α. Our results, thus, indicate that broussoflavonol B is a potent growth inhibitor of ER-negative breast cancer stem-like cells and provide a rationale for pre-clinical and clinical evaluation of broussoflavonol B for breast cancer therapy.

The improvement of detection and eradication of minimal residual disease, to reduce local and distant relapse after primary therapy, is one of the major challenges in the management of squamous cell carcinoma of the head and neck (HNSCC). This paper describes perspectives arising from the use of monoclonal antibodies (MAbs) E48 and U36 directed against HNSCC-associated antigens, and the molecular characterization of these antigens. Novel strategies for the detection of minimal residual disease are outlined and comprise the use of immunocytochemistry in combination with automated image analysis, and the use of an E48-specific reverse transcriptase-polymerase chain reaction (RT-PCR) method. These methods have potential for the detection of single HNSCC cells in lymph nodes, bone marrow and peripheral blood, and may contribute to the better staging of head and neck cancer in the near future. Besides this, preclinical and clinical data on HNSCC targeting with radiolabelled MAbs E48 and U36 are summarized, illustrating the perspectives of systemic adjuvant radioimmunotherapy with these MAbs.

In a recent paper entitled "Circulating 25-Hydroxyvitamin D and the Risk of Pancreatic Cancer," Stolzenberg-Solomon et al. reported that the odds ratio for diagnosis of pancreatic cancer shows a "statistically significant" precipitous jump of more than a factor of 2 at the highest presented concentrations of100 nmol/l. This was one of six related studies of the relation of 25-hydroxyvitamin D and six types of rarer cancers, collected by the Vitamin D Pooling Project (VDPP). An alternative analysis of the presented data suggests that the reported two-fold higher risk at the highest serum 25(OH)D level in the pancreatic cancer study is most likely a statistical artifact associated with the chosen cut-off point groupings and there is no U-shaped curve to be explained.

Combined modality therapy using both chemotherapy and radiation has proved superior over radiation therapy alone for a variety of cancer types. While the locoregional control and survival benefits have been established, there is still much room for improvement both in terms of cancer control and normal tissue toxicity, i.e. the therapeutic ratio. Recently, the pace of research and development of both conventional cytotoxic and molecularly targeted radiosensitizers has been staggering. The aim of this paper is to bring the reader up to date on the clinical status of four promising new radiosensitizers: novel camptothecin analogs and inhibitors of poly(ADP-ribose) polymerase, histone deacetylase, and heat-shock protein 90.

It is possible that macrophages may be effective for cancer treatment because once activated, lung macrophages have enhanced contact with lung tumor cells and have a cytotoxic effect. In this paper, we report that nitric oxide (NO) produced by lung macrophages activated with lipopolysaccharide (LPS) suppressed cell growth of human lung adenocarcinoma cells.A549, a lung adenocarcinoma cell line, was cultured with NR8383, a rat alveolar macrophage cell line, in the presence and absence of LPS. The effect of LPS on the growth rate of A549 cells was examined as a function of NO production under cell-to-cell contact conditions.NR8383 cells showed potent cytostatic and cytocidal effects on A549 cells when both cells were co-cultured in the presence of LPS. These effects were mainly due to the production of NO, but another possible mechanism, such as cell-to-cell contact, may also be involved.Activation of alveolar macrophages by LPS suppresses the growth of lung carcinoma cells via NO production under cell-to-cell contact conditions.

Molecularly targeted therapeutics provides potentially more reliable performance while significantly reducing toxicity in comparison with chemotherapy. For cancer signaling networks which are usually complex, multiple molecules should be simultaneously targeted in order to stay in tune with the control mechanisms of the network and to achieve the maximum synergistic effects. Mathematical modeling and computer simulation are important in reproducing the dynamics of the network, some of which may correspond to healthy or cancer phenotypes. More importantly, the effects of multiple molecules can be simulated by perturbing many parameters in the model. In this paper, through the example of the mTOR signaling pathway, we demonstrate that computational analysis can provide great insights into cancer pathogenesis and the possible therapeutic interventions. In particular, we discovered a composite parameter which summarizes the synergistic effects of four different parameters. The geometry of the parameter space could be helpful in the development of a low dosage, minimal toxicity drug to cure cancer.

Concurrent presence of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC) patients is relatively rare and their appearance is believed to be mutually exclusive. Tumours harbouring KRAS mutation are perceived as not being capable of response to tyrosine kinase inhibitor (TKI) therapy.This paper presents 5 case reports of patients with tumours harbouring multiple EGFR and/or KRAS mutations. There were 3 patients with EGFR mutations (2 x exon 19 deletions, 1 x L858R) combined with KRAS mutations (2 x Gly12Asp, 1 x Gly12Val), 1 patient with two EGFR mutations (exon 19 deletion + L858R) and 1 patient with two KRAS mutations (Ala11Pro + Gly12Val).All EGFR(+)/KRAS(+) patients had initially showed positive response to TKI treatment. The EGFR(+)/EGFR(+) patient has exhibited strong rash and good response with the best survival, while the KRAS(+)/KRAS(+) patient did not respond to TKI therapy.EGFR(+)/KRAS(+) combination does not necessarily pose a negative prediction. This is probably due to the multiclonal character of the tumour displaying partial response in the EGFR(+) subpopulation.

Gamma-glutamyltransferase (GGT) is a key enzyme involved in glutathione metabolism and whose expression is often significantly increased in human malignancies. In the past years, several studies focused on the possible role of GGT in tumor progression, invasion and drug resistance. The involvement of a pro-oxidant activity of GGT, besides its early recognized contributions to cellular antioxidant defenses, has been repeatedly documented. GGT-derived pro-oxidants can modulate important redox-sensitive processes and functions of the cell, with particular reference to its proliferative/apoptotic balance, which has obvious and important implications in tumor progression and drug resistance. In addition, the specificity of the enzymatic reaction carried out by GGT suggests that suitable pro-drugs could be selectively metabolized (activated) by GGT expressed in tumor tissue. This paper is a review of the recent investigation in the field, focusing on the potential role of GGT as a diagnostic/prognostic marker, as well as a target for anticancer treatments.

The current model of gastric carcinogenesis comprises the interaction of multiple risk factors. Besides Helicobacter pylori (H. pylori) infection as the major risk factor for gastric carcinogenesis, environmental factors (e.g. high saline- or nitrosamine-containing food) and genetic susceptibility contribute to the development of gastric cancer (GC). It has been established that the topographical pattern of gastritis and its immune response are the main causes for the persistence of bacteria and the final clinical outcome. Regulatory immune cells, mostly regulatory FOXP3(+)CD4(+)CD25(+high) T-cells (Treg cells), have been identified as the major regulatory component of the adaptive immune response and involved in H. pylori-related inflammation and bacterial persistence. The functional activity of these cells is either mediated by direct cell-cell contact or by the secretion of the immune-modulating cytokines TGF-beta1 and IL-10. Based on the differentiation process, Treg cells comprise various lineages that differ in the expression of cell surface marker and pattern of secreted cytokines. Numerous studies have demonstrated important functions of Treg cells for controlling acute and chronic inflammatory processes. This paper reviews the role of Treg for gastric carcinogenesis and precursor lesions related to H. pylori.

Patients with type 2 diabetes mellitus (T2DM) as well as patients with obesity have increased cancer mortality. In a previous paper we suggested that there was a trend for decreased mortality in obese individuals with T2DM. The aim of the new analyses was to investigate the same relationship after increasing our sample size and extending our follow-up period.1353 patients were followed prospectively as part of the ZODIAC study. The cancer mortality rate was evaluated using standardized mortality ratio (SMR) and its association with BMI (kg/m(2)) and obesity (30 kg/m(2)) with Cox proportional hazard analysis.After a median follow-up time of 9.8 years, 570 patients had died, of whom 122 died from malignancy. The SMR for cancer mortality was 1.47 (95%CI 1.22-1.76). BMI and obesity were not associated with cancer death.The trend towards an inverse relationship between obesity and cancer mortality as reported previously disappeared after increasing sample size and follow-up to 9.6 years.

The ultraviolet-B (UVB)-vitamin D-cancer hypothesis was proposed in 1980. There have been numerous ecological, observational and other studies of the hypothesis. There are about 14 types of cancer for which it seems to apply: bladder, breast, colon, endometrial, esophageal, gallbladder, gastric, ovarian, pancreatic, rectal, renal and vulvar cancer and both Hodgkin's and non-Hodgkin's lymphoma. Nonetheless, the hypothesis has not yet been accepted by public health agencies. Some of the reasons for this include a distrust of ecological studies, some mistrust of observational studies, and the existence of just one positive randomized controlled trial, an analysis of a vitamin D and calcium supplementation study involving post-menopausal women in Nebraska. Paradigm shifts such as this generally take time, in part due to opposition from those content with the status quo. In this paper, results of ecological studies in the United States using summertime solar UVB as the index of vitamin D production, which is highly asymmetrical with respect to latitude, and indices for other cancer risk-modifying factors (air pollution, alcohol consumption, dietary iron and zinc, ethnic background, socioeconomic status, smoking and urban/rural residence) are discussed in terms of supporting the hypothesis. These studies were not considered while other ecological studies were examined in recent critiques of the hypothesis. While additional randomized controlled trials would, of course, be helpful, the current evidence seems to satisfy the criteria for causality as outlined by A. Bradford Hill.

Peritoneal dissemination of gastric cancer is a refractory disease. This paper focuses on the efficacy of actin-binding marine macrolide latrunculin A, which quickly inhibits actin polymerization and disrupts the function of the actin cytoskeleton. The effects of latrunculin A on cell viability in vitro were evaluated by treatment of MKN45 or NUGC-4 cell cultures. An in vitro viability assay demonstrated an anticancer effect of latrunculin A in a dose-dependent manner. Latrunculin A induced acute cell injury and programmed cell death through activating the caspase-3/7 pathway. In vivo, MKN45 or NUGC-4 cells were intraperitoneally inoculated into nude mice, as a model of peritoneal dissemination. Intraperitoneal (i.p.) injection of latrunculin A significantly improved survival rate in mice without any major side-effects. Data indicated that latrunculin A has strong anticancer effects, and it may be a new candidate i.p. drug against peritoneal dissemination of gastric cancer in humans.

The association between 5-fluorouracil (5-FU)-related enzyme activity and the sensitivity of bladder urothelial carcinoma (BUC) to 5-FU were investigated, and methods to improve 5-FU sensitivity were analyzed.Tumor specimens were obtained from 127 patients. Orotate phosphoribosyl transferase (OPRT) activity was analyzed by the paper disc method and thymidine phosphorylase and dihydropyrimidine dehydrogenase (DPD) activities were measured by ELISA. 5-FU sensitivity was assessed in 99 cases by an in vitro chemosensitivity test.A significant positive correlation between OPRT activity level and the sensitivity of BUC to 5-FU was identified. Moreover, the combination of 5-FU and 5-chloro-2,4-dihydroxypyrimidine significantly enhanced 5-FU sensitivity in BUC, particularly in cases showing higher DPD activity.OPRT was the most important enzyme in predicting sensitivity to 5-FU in BUC. These results may have implications for tailor-made medication using 5-FU-related compounds as postoperative adjuvant chemotherapy in BUC patients.

We report on radiological abnormalities resembling recurrent tumor in adult medulloblastoma receiving intensified chemotherapy and radiotherapy. Evidence provided in this paper confirms previous reports in the pediatric population and suggests that neuroradiologist and medical oncologists should be aware of new possible radiological findings related to aggressive treatments for brain tumors.

Many different single nucleotide polymorphisms (SNPs) genotyping methods have been developed recently. However, most of them are expensive. Using restriction enzymes for SNP genotyping is a cost-effective method. However, restriction enzyme mining for SNPs in a genome sequence is still challenging for researchers who do not have a background in genomics and bioinformatics. In this review, the basic bioinformatics tools used for restriction enzyme mining for SNP genotyping are summarized and described. The objectives of this paper include: i) the introduction of SNPs, genotyping and PCR-restriction fragment length polymorphism (RFLP); ii) a review of components for genotyping software, including tools for primer design only or restriction enzyme mining only; iii) a review of software providing the flanking sequence for primer design; iv) recent advances in PCR-RFLP tools and natural and mutagenic PCR-RFLP; v) highlighting the strategy for restriction enzyme mining for SNP genotyping; vi) a discussion of potential problems for multiple PCR-RFLP. The different implications for restriction enzymes on sense and antisense strands are also discussed. Our PCR-RFLP freeware, SNP-RFLPing, is included in this review to illustrate many characteristics of PCR-RFLP software design. Future developments will include further sophistication of PCR-RFLP software in order to provide better visualization and a more interactive environment for SNP genotyping and to integrate the software with other tools used in association studies.

The family of human matrix metalloproteinases (MMPs) comprises several tightly regulated classes of proteases. These enzymes and their specific inhibitors play important roles in tumour progression and the metastatic process by facilitating extracellular matrix degradation. As scientific understanding of the MMPs has advanced, therapeutic strategies focusing on blocking these enzymes by matrix metalloproteinase inhibitors have rapidly developed. Low molecular weight tissue inhibitors of matrix metalloproteinase (TIMPs) represent a new therapeutic approach for the treatment of individual types of cancer. This paper aims to briefly summarize current knowledge about the role of MMPs in select non- tumorous lesions, tumor invasion and metastasis. The perspectives in therapeutic intervention in cancer are also mentioned. The role of MMPs in diagnosis and prognosis of colorectal and thyroid cancer is discussed in detail.

The incidence of mesothelioma is estimated to rise sharply worldwide, including Japan, in the next two decades. Molecular and proteomic studies are urgently required to elucidate the pathobiology of malignant mesothelioma. This paper describes the characterization of novel human malignant pleural mesothelioma cell lines representing the sarcomatoid, epithelioid and biphasic subtypes.Established pleural effusion fluid cell lines were observed using phase-contrast microscopy and transmission electron microscopy. The immunoreactivity of the cells was evaluated using immunohistochemistiy, FACS analysis and Western blotting. The expression of SV40 large cell antigen and the EGFR mutation status were also analyzed.The cell lines had different morphological and immunophenotypic characteristics. All cell lines showed immunophenotypic marker expression of vimentin, mesothelin and N-cadherin, but no expression of CEA or E-cadherin. At the electron microscopic level, a cell surface rich in microvilli confirmed mesothelial origin of the cell lines. Karyotype analyses showed complex abnormalities in all cell lines. Neither EGFR mutations relevant to tyrosine kinase inhibitor responsiveness nor the expression of SV40 large cell antigen was detected in any of the cell lines.FACS analysis is more sensitive for evaluating mesothelin expression than immunohistochemistry of cut specimens. Irrespective of the expression of EGFR on FACS analysis, no EGFR mutation was detected. These three cell lines may be useful for studying cellular, molecular and genetic aspects of mesothelioma.

Neuroendocrine tumours (NET) are rare tumours that occur most commonly in the GI tract. Various labelled somatostatin analogues are used to image NET expressing somatostatin receptors (SSTR). In traditional nuclear medicine, most peptides used in imaging NET have been labelled with indium-111, the commonest being indium-111-octreotide (111In-octreotide). Unfortunately, the unfavourable physical qualities of In-111 make it unsuitable for detecting small tumour deposits. The recent introduction of gallium-68-1,4, 7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (gallium-68-DOTA) compounds for positron emission tomography (PET) imaging has significantly improved the quality of imaging NET through improved resolution of PET and higher affinity of the new generation of peptides to SSTR. In the present paper, we discuss the clinical and research applications of PET radio-tracers for evaluating NET, in particular gallium-68-DOTA compounds. The recent introduction of PET imaging with gallium-68 has major bearings in current and future clinical practice. Its labelling with DOTA compounds has cleared the way for somatostatin receptor imaging with a viable PET agent, with all its inherent imaging advantages compared to single photon imaging. The pre-clinical and clinical applications of this technique has been successful in a variety of tumours, particularly NET and its labelling with other ligands and molecules will improve the management of other tumours and the assessment of infection.

More than two-thirds of patients diagnosed with esophageal cancer will have unresectable disease. The objective of this article is to review the clinical trials utilizing cytotoxic chemotherapy in patients with recurrent and metastatic esophageal cancer. A computerized (MEDLINE) search was performed to identify papers published on this topic between 1966 and 2007. A total of 96 trials were subsequently identified. Two randomized trials compared palliative chemotherapy with best supportive care in 180 patients with advanced esophageal cancer. Effectiveness and side-effects were evaluated in 49 phase II studies and 3 randomized phase III trials. Combination chemotherapy as compared to monochemotherapy is associated with significantly higher response rates but nevertheless results in similar survival. CF (cisplatin and 5-fluorouracil) currently represents one of the most effective regimens for advanced esophageal cancer, while among the newer combinations, irinotecan or taxane-based regimens have also given promising results. Prognosis for the majority of patients, however, remains poor as increases in survival were moderate at best.

During the complex process of melanoma cell detachment from the primary tumor and subsequent metastasis, different cell surface proteins are involved in tumor cell interactions with extracellular matrix (ECM) components and surrounding cells. Melanoma cells are able to vary their expression patterns of adhesion proteins and proteases or peptidases in different stages of tumor development.This paper describes the detection of intercellular adhesion molecule-1 (ICAM-1) and aminopeptidase N (APN) on melanoma cells by immunoluminescence. The marker enzyme horseradish peroxidase (HRP) of the secondary antibody (Ab) was used to release luminescence. In addition, APN was detected on intact cells with an activity assay using alanine-p-nitroanilide (Ala-pNA) as substrate including inhibition experiments.The cell surface expression of ICAM-1 and APN on melanoma cells was shown by indirect labelling using two different antibodies for each antigen. The activity and inhibition assays confirmed the immunoluminescent result for APN.Both cell surface proteins have a strong impact on tumor cell behaviour and are typical cell markers indicating a high metastatic tumor stage in melanoma. The extensive characterization of melanoma cells offers the possibility for therapeutic approaches with more than one target molecule. Moreover, increasing insights into the components involved in signal transduction could help to develop specific reagents that inhibit tumor-specific pathways.

Oral mucositis is one of the main complications in non-surgical cancer treatments. It represents the major dose-limiting toxicity for some chemotherapeutic agents, for radiotherapy of the head and neck region and for some radiochemotherapy combined treatments. Many reviews and clinical studies have been published in order to define the best clinical protocol for prophylaxis or treatment of mucositis, but a consensus has not yet been obtained. This paper represents an updated review of prophylaxis and treatment of antineoplastic-therapy-related mucositis using a MEDLINE search up to May 2006, in which more than 260 clinical studies have been found. They have been divided according to antineoplastic therapy (chemotherapy, radiotherapy, chemo-radiotherapy, high-dose chemotherapy). The prophylactic or therapeutic use of the analysed agents, the number of enrolled patients and the study design (randomized or not) were also specified for most studies. Accurate pre-treatment assessment of oral cavity hygiene, frequent review of symptoms during treatment, use of traditional mouthwashes to obtain mechanical cleaning of the oral cavity and administration of some agents like benzydamine, imidazole antibiotics, tryazolic antimycotics, povidone iodine, keratinocyte growth factor and vitamin E seem to reduce the intensity of mucositis. Physical approaches like cryotherapy, low energy Helium-Neon laser or the use of modern radiotherapy techniques with the exclusion of the oral cavity from radiation fields have been shown to be efficacious in preventing mucositis onset. Nevertheless a consensus protocol of prophylaxis and treatment of oral mucositis has not yet been obtained.

Small globular protein (SGP) is an artificially designed protein that forms small pores on lipid bilayer membranes. The anti-tumor effect of SGP has been reported in several papers. However, the exact mechanism underlying SGP-induced cell death remains to be determined.The mechanisms of SGP-mediated cytotoxicity were examined using cultured malignant glioblastoma cells (U87-MG). Morphological changes were observed under a light microscope. Ultrastructural changes were examined by electron microscopy. Changes in membrane permeability were evaluated by measuring the extracellular release of lactate dehydrogenase (LDH) and intracellular calcium concentration ([Ca2+]i). A new cell viability assay was also conducted using DAPI/calcein fluorescent-double staining methods.SGP cytotoxic effects were strongly influenced by fetal bovine serum (FBS) concentration in culture media. After 30 min of incubation, cytotoxic effects were noted at SGP concentrations greater than 1.5 microM. [Ca2+]i increased immediately after SGP addition. Extracellular efflux of LDH increased linearly with SGP doses (r(2) =0.936), and occurred even at concentrations less than 1.5 microM. Non-viable and viable cells were simultaneously detected by fluorescent staining with DAPI and calcein-AM, respectively. After 30 min of incubation with SGP, DAPI-positive nuclei were evident at concentrations higher than 1.5 microM. Cultures were then maintained in 10% FBS-containing media for 24 h before addition of calcein-AM. Calcein-positive cells were found at SGP concentrations lower than 1.5 5M. Cells positive for both DAPI and calcein appeared at a concentration of 1.5 microM.Our results indicate that SGP induces rapid but transient cytotoxicity, which may be beneficial in local therapy of malignant brain tumors.

Camptothecin (CPT) derivatives have emerged as a promising group of chemotherapeutic agents. The FDA has approved the CPT derivatives topotecan and irinotecan for second line treatment of ovarian cancer and metastatic colorectal cancer, respectively. These and other CPT derivatives have become part of the multi-million dollar industry that is dedicated to finding better chemotherapeutic agents with excellent tumor kill and less normal tissue toxicity. In order to reach this goal it is imperative to understand the details of the mechanisms of action and the targets of these drugs, as well as the cellular response to the drugs. Although investigations of CPT date back to the 1960's, most of the studies that have been added to our present knowledge were done in the last 10 years. The purpose of this paper is to review the latest insights into the CPT binding site, CPT-induced gene expression and CPT-induced pathways to apoptosis.

Mucocele of the appendix is a rare lesion, characterized by distension of the lumen due to accumulation of mucus material. Correct preoperative diagnosis is seldom achieved. If left untreated, the mucocele may rupture producing a potentially fatal peritoneal spread. The type of surgical treatment is related to the dimensions and histology of the mucocele. In this paper, the case of a 49-year-old woman, with a previous appendectomy, suffering from a painful mass in the right lower quadrant of the abdomen, is reported. Imaging showed a large, cystic structure at the base of the cecum. Surgery revealed a 8x5.5 cm calcified tumor, which was excided together with the appendiceal remnant. Pathological diagnosis was that of a mucocele arising from the appendiceal stump due to the development of a benign mucinous cystadenoma.

Colorectal cancer is one of the most common neoplasms in Western Countries and ranks second as a cause of death due to cancer. The overall mortality at 5 years is about 40%. Patients with resectable metastatic disease can be cured, but for those who cannot, treatment is purely palliative, and overall survival (OS) is from approximately 7 to 24 months. Infusional regimen with modulated 5Fluorouracil (5FU) gives an objective response rate (RR) of up to 30-40%. The addition of CPT11 or oxaliplatin to 5FU improves RR, time to progression (TTP) and OS with a stabilization of disease (SD) in 40-70% of cases and 20-40%, respectively. The concurrent utilization of selective biological agents as growth factor receptors acting at a molecular level and influencing the processes of tumor formation and growth, increases tumor cell apoptosis and inhibits tumor growth; as a result, the tumor regresses or is inhibited, with consequently prolonged OS and TTP. This paper examines the problem related to the treatment of metastatic colorectal cancer with SD. Current doubts regarding the continuation of one treatment until disease progression (PD) with a risk of toxicity, whether or not to use a less toxic "maintenance" therapy after a fairly aggressive "induction" therapy in "stabilized" responders, or whether to stop the treatment in the presence of a SD confirmed after at least two consecutive evaluations, are present.

Several antitumor drugs have been described to induce nuclear factor kappaB (NF-kappaB), but results about its role in regulating apoptotic cell death are quite controversial. In this paper, we studied NF-kappaB induced by the two anticancer agents Sabarubicin (MEN 10755) and paclitaxel (Taxol) and the effects of its pharmacological inhibition.In the human colon cancer cell line HCT-116, we investigated NF-kappaB activation induced by the two anticancer agents using electrophoretic mobility shift assay (EMSA), while drug-induced cytotoxicity was measured by trypan blue staining. Apoptosis was analyzed using a cell death detection enzyme-linked immunosorbent assay (ELISA) kit, flow cytometry and caspase-3 activation assay.The combination with the NF-kappaB inhibitorparthenolide increased Sabarubicin- but not paclitaxel-induced cell death. EMSA experiments demonstrated that the two antitumor drugs induced NF-kappaB complexes with different kinetics but similar subunit composition. Moreover, Sabarubicin elicited NF-kappaB activation definitely earlier than DNA fragmentation, whereas with paclitaxel the kinetics of the two phenomena were similar.

Not only serum tumor markers, such as carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and carbohydrate antigen (CA) 125, but also serum growth factors have been examined to evaluate tumor stages and to predict the recurrence and metastasis in patients with non-small cell lung cancer (NSCLC) (1-5). In recent years, the analysis of the genome and proteome has advanced remarkably. An array of molecular genetic tumor markers (MGTMs) have been identified based on the biological characterization of tumors, such as tumor development, growth, invasion and metastasis. Molecular genetic tumor marker research has also entered a new era, since comprehensive gene profile analysis using cDNA microarrays and comprehensive protein expression analysis using proteomics technology have been developed. On the other hand, the frequency of lung cancer patients with which various tumor markers are associated is increasing in Japan (6-8). This paper reviews MGTMs characteristic of lung cancer and clarifies the clinical usefulness and applications of MGTM for cancer treatment.

Transformation of normal cells into malignant cancer involves a number of changes in the genome. These changes include chromosomal translocations, exon deletions and gene mutations, to name a few, that result in deregulation of the regulatory circuits of the cell and consequently in profound changes in their antigenic composition, including expression of mutated proteins, overexpression of proteins that are produced at much lesser levels in normal tissue and expression of aberrantly glycosylated proteins. It is well established that these new antigenic entities, referred to as tumor-associated antigens (TAA), are recognized by the immune system and elicit immune reactivity. However, the immune reaction is overpowered by the cancer potential to grow and to metastasize. Cancer immunotherapy aims at boosting the naturally occurring immune response at a level that will prevail over the ability of cancer cells to escape immune attack. After more than 20 years of intense research and a growing number of clinical trials, most of which gave marginal results, it is now clear that the task is not an easy one. However, during the same period of time, we have gained a much better understanding of the mechanisms of tumor growth, the mechanisms by which the immune system is activated or becomes tolerant and of the natural relationship between cancers and the immune system. Also, even though few, some immunotherapy strategies have demonstrated positive clinical responses and are already used as standard therapies. These developments give the impetus to explore and devise new strategies that will by more effective in strengthening the immune reactivity at a level that will counteract the tumor potential. In this paper we review the knowledge gained from basic research related to cancer immunity and from clinical trials. We propose that, based on this knowledge, improved clinical protocols can be elaborated.

A new mathematical model is presented to simulate various changes of cell pools in the T cell immune system with validation procedures imitating viral infections. The present paper focuses on changes during the course of an acute progressive HIV-1 infection. Parameters are optimized by a direct search method and the stability of the model is studied. Mathematical modeling supports the hypothesis that the differentiation blockade is one major reason for the depletion of CD4 cells and the proliferation of CD38 cells in HIV-1 infection. The model appears to be a useful basis for further simulating disturbances of the T cell immune system in other viral infections as well as to elucidate the pathogenesis of various immunological diseases including the development of malignant lymphomas.

A new series of imidazothioxanthones has recently been synthesized as potential anticancer agents with the aim of overcoming drug resistance. The route of synthesis and DNA-binding properties of the compounds were reported previously. This paper describes the general structure-activity relationships for the class of imidazothioxanthones in panels of human and murine tumor cell lines in vitro, and the in vivo activity against human and murine solid tumors of the most potent compound, N-[3-(Dimethylamino)propylo]-11-oxo-11H-benzothiopyrano [3',2':2,3]pyrido[1,2-a]imidazo-2-carboxamide (10a). In addition, the interaction between compound 10a and DNA is also considered in terms of molecular mechanics methods and flexible docking techniques.The cytotoxicity of compounds 10a, 11-oxo-N-[2-(pyrrolidino)ethylo]-11H-benzothiopyrano [3',2':2,3]pyrido[1,2-a]imidazo-2-carboxamide, 11-oxo-N-[2-(piperidino)ethylo]-11H-benzothiopyrano [3',2':2,3]pyrido[1,2-a]imidazo-2-carboxamide and N-[2-(morpholino)ethylo]-11-oxo-11H-benzothiopyrano [3',2':2,3]pyrido[1,2-a]imidazo-2-carboxamide (10c-10e) was assessed in human tumor cell lines and xenografts using the sulforhodamine B assay, MTT assay and the clonogenic assay. The human ovarian xenograft, PXN/109TC, two human breast carcinomas, MT-1 and MCF-7, and the murine colon adenocarcinoma, MAC15A were used for the in vivo testing of compound 10a. In addition, the interaction between compound 10a and DNA is also considered in terms of molecular mechanics methods and flexible docking techniques.Two compounds, 10a and 10c, showed cytotoxic activity below 10 mM in the NCI in vitro screen of 60 human tumor cell lines. The IC50 value of compound 10a was 6.8 mM and that of 10c, 8.3 mM. In addition, both compounds possessed differential activity against leukemia, colon and mammary cancer. The activity pattern was confirmed in two further screens using monolayer and clonogenic, assays. In vivo antitumor studies showed that 10a was active against the human mammary carcinoma MT-1 and murine colon cancer MAC15A. Marginal activity was observed in human ovarian cancer model PXN/109T/C and the compound was inactive in human mammary cancer MCF-7.The results warrant further in vivo testing of 10a in additional human solid tumor models. The molecular modeling showed that the planarity of the chromophore and the side-chain conformation could assist the insertion of compound 10a between the base pairs of the double helix. On the other hand, docking to the nucleotide sequence GGAATTGCCTCA suggested that the molecule could also act as a minor groove binder.

Despite progress in diagnosis and therapy, the prognosis of patients with glioblastoma remains poor. Recently it has been found that the antibacterial agent taurolidine has a direct and selective antineoplastic effect on brain tumor cells by the induction of programmed cell death. This paper reports on intravenous taurolidine treatment in two patients with a progressive glioblastoma despite conventional therapy.Two male patients with histopathologically diagnosed glioblastoma were included. The tumors were progressive despite conventional therapy. Intravenous taurolidine treatment was initiated.The neurological condition and quality of life improved in both patients such that they could be discharged for further outpatient treatment. Follow-up demonstrated partial remission of the tumor in both patients. However, both patients died about 4 months following the start of taurolidine treatment, from pneumonia and acute thrombembolism, respectively.Both patients achieved a transient, marked improvement in quality of life and partial tumor remission. There was a clear response to the taurolidine treatment.