Antitumor agents. Part 186: Synthesis and biological evaluation of demethylcolchiceinamide analogues as cytotoxic DNA topoisomerase II inhibitors

Demethylation of colchiceinamide (2) and its analogues (3-10) afforded a novel class of mammalian DNA topoisomerase II inhibitors (2a-10a) without displaying tubulin inhibitory activity. All target compounds inhibited the catalytic activity of topoisomerase II at drug concentrations at 100 microM. An in vitro cytotoxicity assay indicated that compounds 3a and 8a were strong and tissue-selective cytotoxic agents against the MCF-7 breast cancer cell line (IC50 = 0.36 and 0.48 microgram/mL, respectively) and the CAKI-1 renal cancer cell line (IC50 = 0.72 and 0.96 microgram/mL, respectively).     

Tubulin structure: insights into microtubule properties and functions

The antimicrobial, hemagglutinating and toxic activities of the purple fluid of the sea hare Aplysia dactylomela are described. Intact or dialyzed purple fluid inhibited the growth of species of Gram-positive and Gram-negative bacteria and the action was not bactericidal but bacteriostatic. The active factor or factors were heat labile and sensitive to extreme pH values. The fluid preferentially agglutinated rabbit erythrocytes and, to a lesser extent, human blood cells, and this activity was inhibited by the glycoprotein fetuin, a fact suggesting the presence of a lectin. The fluid was also toxic to brine shrimp nauplii (LD50 141.25 micrograms protein/ml) and to mice injected intraperitoneally (LD50 201.8 +/- 8.6 mg protein/kg), in a dose-dependent fashion. These toxic activities were abolished when the fluid was heated. Taken together, the data suggest that the activities of the purple fluid are due primarily to substance(s) of a protein nature which may be involved in the chemical defense mechanism of this sea hare.     

Expression of interleukin-6 in polymorphic reticulosis--immunohistochemical study of 5 cases

Peripheral T cell lymphoma encompasses lymphomas with a variety of histologic appearances and clinical patterns. Recently, it has been suggested that almost all of the histologic features described under the name of polymorphic reticulosis(PR), lethal midline granuloma, and midline malignant reticulosis can be included in those generally described for malignant lymphomas of peripheral T cell origin(PTCL). There have been few studies of pathogenesis or tissue damage mechanism in PR patients. The need for a precise mechanism for tissue damage has important therapeutic implications. Using immunohistochemical methods with polyclonal anti IL-6 antibody, the authors describe 5 cases of PR with clinically and pathologically typical PR demonstrating a high expression of IL-6. According to classification, 2 cases of grade 1 PR showed the highest expressions, and 2 cases of grade 2 PR with atypical lymphoid cells showed moderate activity, but one case progressed into frank lymphoma(grade 3) and lost IL-6 expression. This strongly implies that some cases of PR have a different mechanism of tissue damage from frank PTCL, despite the one disease spectrum. Further studies on more cases may help clarify the pathogenesis.     

Post-chemotherapy and cytokine pretreated marrow stromal cell layers suppress hematopoiesis from normal donor CD34+ cells

Marrow stromal layers were used to investigate the potential role of negative regulators produced by the marrow microenvironment as one potential cause of hematopoietic suppression after chemotherapy and cytokines. Stromal layers were established from marrow of normal or prechemotherapy donors and breast cancer patients after hematological recovery from one cycle of 5-fluorouracil, leucovorin, doxorubicin, and cyclophosphamide and GM-CSF or PIXY321 (GM-CSF/IL-3 fusion protein). Normal donor CD34+ cells were placed in contact with stromal layers, and the number of colony-forming units for granulocytes and macrophages (CFU-GM) was determined. There were 25-79% fewer CFU-GM in post-chemotherapy stromal layer cocultures than in no chemotherapy cocultures. With neutralizing antibody to TNF-alpha the number of CFU-GM in no chemotherapy and post-chemotherapy stromal cocultures was, respectively, 96 +/- 7% (n = 5) and 142 +/- 8% (n = 5) of the number with no antibody treatment. PIXY321 and GM-CSF pretreated stromal layers also suppressed production of CFU-GM. Anti-TNF-alpha promoted an increase in CFU-GM numbers from GM-CSF, but not PIXY321, pretreated stromal cocultures. The results demonstrate that post-chemotherapy marrow stromal layers were deficient in supporting in vitro hematopoiesis and suggest that negative regulators induced by chemotherapy and cytokines may be one cause for this defect.     

CT combined with arterial portography. A sensitive method for evaluation of liver tumors

During the period 1994-95, 22 patients were examined with CT during arterial portography for evaluation of hepatic tumours. The majority, 20 patients, had metastases from colon cancer. All patients were candidates for liver resection. In the series of patients described here, this process detected additional lesions in four more of the patients than found with any other imaging techniques. This supports that CT during arterial portography is the most sensitive method for detecting small malignant hepatic tumours, and for localizing them in relation to liver segments and major vascular structures. Optimal results are obtained in the absence of diffuse parenchymal disease and portal hypertension. Non-tumourous perfusion defects limit the accuracy of this technique, but such defects have characteristic locations and appearance. In difficult cases the technique should be correlated with ultrasonography and MR.     

Radiofrequency and cryoablation of atrial fibrillation in patients undergoing valvular operations

BACKGROUND: Previous studies have shown that the maze operation can restore sinus rhythm and atrial transport function in patients with chronic atrial fibrillation. The purpose of this study was to test the feasibility of the application of radiofrequency and cryoablation as an alternative to the classic maze operation. METHODS: Twelve patients undergoing mitral valve procedures were included in this study. Radiofrequency and cryoablation were applied to create lesions in both atria to simulate the classic maze operation. RESULTS: There were two surgical deaths. At the mean follow-up of 10.25 months for the remaining 10 patients; 6 were in sinus rhythm, 2 in atrial rhythm, 1 in paroxysmal atrial tachycardia, and 1 in atrial fibrillation. Doppler echocardiography at 6-month follow-up showed emergence of biatrial transport function in 3 patients and right atrial contractility in 8. At 12-month follow-up of 5 patients, Doppler echocardiography showed biatrial transport function in 3 and right atrial contractility in 4. CONCLUSIONS: Our modified maze procedure during valvular operation is effective for achieving an acceptable success rate to restore sinus rhythm and atrial transport function in patients with chronic atrial fibrillation.     

Functional dissociation between local and systemic immune response during anti-melanoma peptide vaccination

Peptide vaccination against tumor Ags can induce powerful systemic CTL responses. However, in the majority of patients, no tumor regression is noted. To study this discrepancy, we analyzed CTL reactivity in a melanoma patient (F001) vaccinated with g209-2M peptide, a single residue variant of gp100(209-217). G209/g209-2M-reactive CTL were identified in post- but not prevaccination PBL. Limiting dilution analysis identified one predominant CTL clone (C1-35), with TCR Vbeta6s2, recognizing g209/HLA-A*0201-expressing targets. Additionally, two autologous melanoma lines (F001TU-3 and -4) and 20 separate tumor-infiltrating lymphocyte cultures were generated from a fine needle aspirate of a metastatic lesion progressing after initial response to vaccination. Both F001TU did not express gp100 and were not recognized by C1-35. Loss of gp100 by F001TU correlated with a marked reduction of gp100 expression in the same metastatic lesion compared with prevaccination. Thus, ineffectiveness of C1-35 and tumor progression could be best explained by loss of target Ag expression. Interestingly, 12 of 20 tumor-infiltrating lymphocyte cultures recognized F001TU, but none demonstrated g209/g209-2M reactivity, suggesting a functional dissociation between systemic and local immune response. This study suggests that vaccination effects must be analyzed in the target tissue, rather than in the systemic circulation alone.     

Acute liver failure

PURPOSE: This article reviews the literature on radiographic imaging techniques and image interpretation for dental implant treatment. MATERIALS AND METHODS: MEDLINE was used to identify published peer-reviewed literature for this report. RESULTS: Radiographic images are indispensable in the evaluation of osseous structures when planning treatment for dental implants. Potential bone sites for implant placement can be assessed clinically by means of palpation or probing through the mucosa; however, diagnostic imaging provides the best means for indirectly measuring bone dimensions. After healing of the implant site, the application of radiology is useful to verify the amount of bone adjacent to the implant and that the transmucosal abutments fit the implant. Upon completion of the implant prosthesis, radiology may be used to monitor initial and long-term success of implant treatment. CONCLUSION: Recommendations for the application of radiology over the course of treatment are made for various implant cases ranging from the overdenture to the single-tooth implant.