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1.
SH Kaufmann D Peereboom CA Buckwalter PA Svingen LB Grochow RC Donehower EK Rowinsky 《Canadian Metallurgical Quarterly》1996,88(11):734-741
BACKGROUND: Topotecan (TPT) is a topoisomerase I poison that exhibits antineoplastic activity. Analysis of the cytotoxic effects of combinations of TPT and other anticancer agents has been limited. PURPOSE: We assessed the cytotoxic effects produced by combinations of TPT and other antineoplastic agents in experiments involving multiple human cancer cell lines of diverse histologic origins. METHODS: The cytotoxic effects of various antimetabolites (fluorouracil, methotrexate, or cytarabine), antimicrotubule agents (vincristine or paclitaxel [Taxol]), DNA alkylating agents (melphalan, bis[chloroethyl]nitrosourea [BCNU], or 4-hydroperoxycyclophosphamide [4HC]), and a DNA-platinating agent (cisplatin), alone and in combination with TPT, were measured in clonogenic (i.e., colony-forming) assays. HCT8 ileocecal adenocarcinoma, A549 non-small-cell lung carcinoma, NCI-H82ras(H) lung cancer, T98G glioblastoma, and MCF-7 breast cancer cell lines were used in these assays. The data were analyzed by the median effect method, primarily under the assumption that drug mechanisms of action were mutually nonexclusive (i.e., completely independent of one another). For each level of cytotoxicity (ranging from 5% to 95%), a drug combination index (CI) was calculated. A CI less than 1 indicated synergy (i.e., the effect of the combination was greater than that expected from the additive effects of the component agents), a CI equal to 1 indicated additivity, and a CI greater than 1 indicated antagonism (the effect of the combination was less than that expected from the additive effects of the component agents). RESULTS: When the mechanisms of drug action were assumed to be mutually nonexclusive, virtually all CIs for combinations of TPT and either antimetabolites or antimicrotubule agents revealed cytotoxic effects that were less than additive. The CIs calculated at low-to-intermediate levels of cytotoxicity for combinations of TPT and the DNA alkylating agents melphalan, BCNU, and 4HC also showed drug effects that were less than additive; in most cases, however, nearly additive or even synergistic effects were observed with these same drug combinations at high levels of cytotoxicity (i.e., at > or = 90% inhibition of colony formation). Results obtained with combinations of TPT and cisplatin varied according to the cell line examined. With A549 cells, less than additive effects were seen at low-to-intermediate levels of cytotoxicity, and more than additive effects were seen at high levels of cytotoxicity. With NCI-H82ras(H) cells, synergy was observed over most of the cytotoxicity range. CONCLUSIONS AND IMPLICATIONS: TPT cytotoxicity appears to be enhanced more by combination with certain DNA-damaging agents than by combination with antimetabolites or antimicrotubule agents. Interactions between TPT and other drugs can vary depending on the cell type examined. Further investigation is required to determine the basis of the observed effects and to determine whether these in vitro findings are predictive of results obtained in vivo. 相似文献
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PE Sipila VJ Wiebe GB Hubbard SK Koester VD Emshoff JU Maenpaa GT Wurz RC Seymour MW DeGregorio 《Canadian Metallurgical Quarterly》1993,(15):2138-2144
The effects of long-term tamoxifen exposure on cell growth and cell cycle kinetics were compared between oestrogen receptor (ER)-positive (MCF-7) and ER-negative (MDA-MB-231) cell lines. In the MCF-7 cell line, prolonged tamoxifen exposure (0.5 mumol/l for > 100 days) blocked cells in G0-G1 of the cell cycle, and slowed the doubling time of cells from 30 to 59 h. These effects corresponded to an increase in the cellular accumulation of tamoxifen over time [mean area under concentration curve (AUC) = 77.92 mumoles/10(6)/cells/day]. In contrast, in the MDA-MB-231 cell line, long-term tamoxifen exposure had no obvious effect on the doubling time, and reduced cellular tamoxifen accumulation (mean AUC = 50.50 mumoles/10(6)/cells/day) compared to the MCF-7 cells. Flow cytometric analysis of MDA-MB-231 cells demonstrated that a new tetraploid clone emerged following 56 days of tamoxifen exposure. Inoculation of the MDA-MB-231 tetraploid clone and MDA-MB-231 wildtype cells into the opposite flanks of athymic nude mice resulted in the rapid growth of tetraploid tumours. The tetraploid tumours maintained their ploidy following tamoxifen treatment for nine consecutive serial transplantations. Histological examination of the fifth transplant generation xenografts revealed that the tetraploid tumour had a 25-30 times greater mass, area of haemorrhage and necrosis, a slightly higher mitotic index and was more anaplastic than the control neoplasm. The control wildtype MDA-MB-231 tumours maintained a stable ploidy following tamoxifen treatment until the eighth and ninth transplantation, when a tetraploid population appeared, suggesting that tamoxifen treatment may select for this clone in vivo. These studies suggest that prolonged tamoxifen exposure may select for new, stable, fast growing cell clones in vitro as well as in vivo. 相似文献
4.
OL Lopez RP Brenner JT Becker RF Ulrich F Boller ST DeKosky 《Canadian Metallurgical Quarterly》1997,48(6):1521-1525
We examined whether either psychotic features (e.g., delusions and hallucinations) or EEG abnormalities are associated with more rapid progression of Alzheimer's disease (AD). AD patients with psychosis have exhibited more EEG abnormalities than those without psychosis, and both abnormal EEG and psychosis have been noted to be predictors of functional and cognitive decline in AD. Ninety-five probable AD patients participating in a longitudinal study of dementia had an EEG and a semistructured psychiatric interview at baseline. Using EEG spectral analysis, we classified records as normal/abnormal based on the parasagittal mean frequency. Patients with abnormal EEGs were more functionally (e.g., Blessed Rating Scale for activities of daily living) and cognitively (e.g., Mini-Mental State) impaired than patients with normal EEG. AD patients with psychosis were only more functionally impaired than patients without psychosis. A two-factor analysis showed no interaction between abnormal EEG and psychosis. In addition, using a Cox proportional hazard model adjusted for age and education, the presence of an abnormal EEG or psychotic symptom at study entry was associated with higher risk of reaching severe cognitive and functional impairment during follow-up. Neither abnormal EEG nor the presence of psychosis predicted death. These results indicate that both abnormal EEG and psychosis are independent predictors of disease progression but not of physical survival. 相似文献
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Dynamic cardiomyoplasty (DCM) involves the electrical stimulation of a pedicled latissimus dorsi muscle flap wrapped around the falling ventricle as a means of cardiac assist. To further elucidate a potential neurohumoral mechanism for improvement of cardiac output after myoplasty, we evaluated the hemodynamic effects of in situ stimulation of the latissimus dorsi muscle (in the absence of cardiomyoplasty). In seven mongrel dogs, a nerve cuff electrode (Medtronic 6901) was placed around the left thoracodorsal nerve (TDN). This was attached to a pulse generator (Medtronic, Itrel 7420), delivering a 4.0 volt, 0.19 second on, 0.81 second off, 33 Hz, 210 microsecond pulse width, cyclic bursts similar to that used in DCM. Stroke volume index (SVI) and other hemodynamic parameters as well as plasma norepinephrine (NE) levels were measured at five stages: baseline, stimulator on at 0, 2, and 5 minutes, and stimulator off at 30 minutes after. The animals were then subjected to 4 weeks of rapid pacing at 240 beats/min (Medtronic 8329) to induce heart failure, and as the rapid pacing was discontinued, measurements were repeated as above. After rapid pacing, cardiac function was significantly depressed, and NE was elevated (133 +/- 69 versus 500 +/- 353 pg/mL, p < 0.05). In the normal hearts, TDN stimulation increased SVI, heart rate, systemic pressure, and NE levels. In heart failure, however, no significant changes in cardiac function and NE levels were noted. In conclusion, our data indicate that in the normal hearts, afferent impulses from TDN stimulation alone may augment cardiac function by means of a neurohumoral effect that is not seen in severe heart failure. The implications of these findings in DCM are discussed. 相似文献
6.
MA Steller KJ Gurski M Murakami RW Daniel KV Shah E Celis A Sette EL Trimble RC Park FM Marincola 《Canadian Metallurgical Quarterly》1998,4(9):2103-2109
Human papillomavirus (HPV) infection has been causally associated with cervical cancer. We tested the effectiveness of an HLA-A*0201-restricted, HPV-16 E7 lipopeptide vaccine in eliciting cellular immune responses in vivo in women with refractory cervical cancer. In a nonrandomized Phase I clinical trial, 12 women expressing the HLA-A2 allele with refractory cervical or vaginal cancer were vaccinated with four E786-93 lipopeptide inoculations at 3-week intervals. HLA-A2 subtyping was also performed, and HPV typing was assessed on tumor specimens. Induction of epitope-specific CD8+ T-lymphocyte (CTL) responses was analyzed using peripheral blood leukapheresis specimens obtained before and after vaccination. CTL specificity was measured by IFN-gamma release assay using HLA-A*0201 matched target cells. Clinical responses were assessed by physical examination and radiographic images. All HLA-A*0201 patients were able to mount a cellular immune response to a control peptide. E786-93-specific CTLs were elicited in 4 of 10 evaluable HLA-A*0201 subjects before vaccination, 5 of 7 evaluable HLA-A*0201 patients after two vaccinations, and 2 of 3 evaluable HLA-A*0201 cultures after all four inoculations. Two of three evaluable patients' CTLs converted from unreactive to reactive after administration of all four inoculations. There were no clinical responses or treatment toxicities. The ability to generate specific cellular immune responses is retained in patients with advanced cervical cancer. Vaccination with a lipidated HPV peptide epitope appears capable of safely augmenting CTL reactivity. Although enhancements of cellular immune responses are needed to achieve therapeutic utility in advanced cervical cancer, this approach might prove useful in treating preinvasive disease. 相似文献
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BACKGROUND: Since its foundation in 1960, the International Society of Nephrology (ISN) has pursued the worldwide advancement of education, science and patient care in nephrology. This goal was achieved by means of the Society's journal and the organization of international congresses and symposia. In order to better reach its colleagues and patients in economically less developed countries, the ISN expanded its activities as of 1980 by a large number of specific programs aimed at these regions. METHODS: The first phase of activities included teaching programs, fellowship and visiting scholar programs, and the provision of travel grants to enhance accessibility to the ISN congresses. A second phase consisted of the creation of a library enhancement program, a commission on acute renal failure and--to improve the organization and efficiency--a central commission on global advancement of nephrology (COMGAN). Currently, a third phase has been entered in which all activities have been intensified: (1) under the guidance of COMGAN, supported by a large number of teaching programs and fact finding missions; (2) by establishing a renal sister program; and (3) by initiating commissions on informatics and on clinical trials. RESULTS: As a result, the ISN has reached most parts of the world, previously deprived of contact with renal science and renal patient care. The fellowship program now counts 160 fellows, who spend one or two years in training. The library enhancement program reaches 218 institutions worldwide. ISN membership has soared over the past two years with over 2,500 new members, mostly in the developing countries. They receive Kidney International and other relevant forms of information. Thus far, 135 pairs of renal units in developing and developed countries have been linked for support on a more continuous basis. ISN-sponsored congresses, symposia, and courses are being held in increasing numbers in the developing world. In many of its activities, the ISN closely collaborates with sister organizations, which also contribute financially. In total, the ISN spends annually over $1 million US from its own budget on the programs described above. CONCLUSION: The various programs and initiatives are proving helpful in advancing renal medicine in areas in need. Expansion into supporting similar programs within other medical subspecialties is being explored. 相似文献
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