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161.
Giuseppe Frasci Giuseppe D'Aiuto Pasquale Comella Renato Thomas Immacolata Capasso Gerardo Botti Giuseppina Rosa Cortino Maurizio Di Bonito Rosaria Rubulotta Paolo Vallone Giuseppe Comella 《Oncology》2002,62(1):25-32
PURPOSE: To define the cyclophosphamide (CTX) maximal tolerated dose when combined with fixed doses of gemcitabine, fluorouracil (5-FU) and folinic acid (leucovorin, LFA) in metastatic breast cancer patients pretreated with anthracyclines and taxanes. METHODS: Metastatic breast cancer patients aged < or = 75 years, with ECOG performance status 0-2, were eligible, provided that they had received previous anthracycline- and taxane-based chemotherapy for the advanced disease. Chemotherapy consisted of gemcitabine 1,000 mg/m(2), 5-FU 425 mg/m(2), LFA 100 mg/m(2) and escalating doses of CTX, starting from 500 mg/m(2), on days 1 and 8 every 3 weeks. The dose escalation was stopped if dose-limiting toxicity (DLT) occurred in > 33% of patients of a given cohort. After the definition of DLT, a further escalation with the addition of granulocyte colony-stimulating factor (G-CSF; on days 3-5 and 10-12) was planned. RESULTS: Since March 1999, 69 patients have entered this trial through seven different cohorts. The dose escalation was stopped at the CTX dose of 600 mg/m(2) since 3/6 patients showed DLT. A further dose escalation was attempted in the presence of G-CSF support. A CTX dose of 800 mg/m(2) proved to be safe and was chosen for the phase II. A total of 33 patients were treated at this dose level. The treatment was fairly well tolerated, grade 3-4 neutropenia and thrombocytopenia occurring in 38 and 16% of patients, respectively. No cases of sepsis or bleeding were registered. Four patients required a packed red blood cell transfusion. Severe nonhematologic toxicity was also uncommon, occurring in 10 patients. Three complete and 24 partial responses were recorded for an overall response rate of 38% (95% CI = 26-50). Two complete and 12 partial responses were recorded in the 33 patients treated in the phase II for an overall response rate (ORR) of 42% (95% CI = 25-61). CONCLUSIONS: The gemcitabine-CTX-5-FU/LFA combination is a well-tolerated treatment for poor-prognosis breast cancer patients with previous exposure to anthracyclines and taxanes. With the addition of G-CSF, a cumulative CTX dose of 1,600 mg/m(2) can be safely delivered every 3 weeks. The evidence of an ORR approaching 40% is very promising and justifies further evaluations in this subset of patients. 相似文献
162.
Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. 总被引:14,自引:7,他引:14
M Colleoni A Rocca M T Sandri L Zorzino G Masci F Nolè G Peruzzotti C Robertson L Orlando S Cinieri Braud F de G Viale A Goldhirsch 《Annals of oncology》2002,13(1):73-80
BACKGROUND: Anticancer chemotherapy is thought to be effective by means of direct cytotoxicity on tumor cells. Alternative mechanisms of efficacy have been ascribed to several common anticancer agents, including cyclophosphamide (CTX), methotrexate (MTX), anthracyclines and taxanes, postulating an antiangiogenic activity. PATIENTS AND METHODS: We evaluated the clinical efficacy and impact on serum vascular endothelial growth factor (VEGF) levels of low-dose oral MTX and CTX in patients with metastatic breast cancer. MTX was administered 2.5 mg bd on days 1 and 2 each week and CTX 50 mg/day administered continuously. RESULTS: Sixty-four patients were enrolled, 63 were evaluable: Eastern Cooperative Oncology Group (ECOG) performance status 0-1, > or =2 sites of metastatic disease (n = 50 patients), progressive disease at study entry (n = 51), 1 regimen for metastatic disease (n = 32) and > or =2 regimens (n = 20). Among the 63 evaluable patients, there were two complete remissions (CR), 10 partial remissions (PR) for an overall response rate of 19.0% (95% CI 10.2% to 30.9%) and an overall clinical benefit (CR+ PR+ stable disease >24 weeks) of 31.7% (95% CI 20.6% to 44.7%). Grade > or =2 leucopenia was registered in only 13 patients. The median serum VEGF level for the subgroup of patients on treatment for at least 2 months decreased with treatment from 315 pg/ml (95% CI 245 to 435) at baseline to 248 pg/ml (95% CI 205 to 311) at 2 months (P <0.001). Both responders and non-responders showed similar reductions in serum VEGF (P = 0.78). After 6 months patients still on treatment had a median VEGF level of 195 pg/ml (95% CI 96 to 355), which was significantly lower than the median baseline values (P = 0.001). CONCLUSIONS: Continuously low-dose CTX and MTX is minimally toxic and effective in heavily pretreated breast cancer patients. A drop in VEGF was associated with the treatment and so alternative hypotheses, other than that of direct toxicity on tumor cells, must be favored when trying to explain the anticancer effect. 相似文献
163.
D Cardinale M T Sandri A Martinoni E Borghini M Civelli G Lamantia S Cinieri G Martinelli C Fiorentini C M Cipolla 《Annals of oncology》2002,13(5):710-715
BACKGROUND: High-dose chemotherapy (HDC) has been widely utilized in high-risk breast cancer, but it may induce cardiac toxicity. Cardiac dysfunction may become evident weeks or months after HDC and, to date, no early markers of myocardial injury that are able to predict late ventricular impairment are available. We investigated the role of plasma troponin I (TnI) in this setting. PATIENTS AND METHODS: We measured TnI plasma concentration after HDC in 211 high-risk breast cancer women (46 +/- 11 years, mean +/- SD). According to TnI value (< 0.5 or > or = 0.5 ng/ml), patients were allocated into a troponin positive (TnI+; n = 70) and a troponin negative (TnI-; n = 141) group. All patients underwent left ventricular ejection fraction (LVEF, Echo) examination during the following 12 months. RESULTS: LVEF progressively decreased in the TnI+ group but not in the TnI- group. In TnI+ patients a close relationship between the TnI increase, as well as the number of positive TnI assays, and the maximal LVEF decrement, was found (r = -0.92, P < 0.0001 and r = -0.93, P < 0.0001, respectively). CONCLUSIONS: In our population, the elevation of TnI soon after HDC accurately predicts the development of future LVEF depression. In this setting, TnI can be considered a sensitive and reliable marker of myocardial damage with relevant clinical and prognostic implications. 相似文献
164.
Different Effects of Regenerative and Direct Mitogenic Stimuli on the Growth of Initiated Cells in the Resistant Hepatocyte Model 总被引:2,自引:0,他引:2
Pierpaolo Coni Giuseppina Pichiri-Coni Marcello Curto Gabriella Simbula Laura Giacomini Dittakavi S. R. Sarma Giovanna M. Ledda-Columbano Amedeo Columbano 《Cancer science》1993,84(5):501-507
The possible mechanism(s) responsible for the different effects exerted by proliferative stimuli of different nature on the appearance of enzyme-altered hepatic foci, were investigated in male Wistar rats. Rats given an initiating dose of diethylnitrosamine (150 mg/kg body weight) were fed a diet containing 0.03% acetylaminofluorene for 2 weeks. Between the first and the second week, cell proliferation was induced by a proliferative stimulus of compensatory type (partial hepatectomy) or by a direct mitogenic stimulus (lead nitrate, 100 μmol/kg). The effect of the two different proliferative stimuli on the appearance of γ -glutamyl transferase-positive foci was monitored by killing the rats for examination at 1, 2, 3, 5, and 6 days after the induction of cell proliferation. The results indicate that while enzyme-altered hepatocytes can be observed as early as 3 days after partial hepatectomy and are characterized by a rapid growth, direct hyperplasia did not exert any effect on the growth capacity of initiated cells. No effect of lead nitrate-induced hyperplasia was observed following three administrations of the mitogen. When platelet-poor plasma taken from animals exposed to the different proliferative stimuli was tested in primary cultures of hepatocytes, it was found that it induced a significant increase in the labeling index of normal hepatocytes. However, while serum taken 6 days after partial hepatectomy was still able to induce a significant increase in the labeling index, platelet-poor plasma from lead-treated rats had lost part of its effect at 5 days after treatment. The inability of direct hyperplasia to stimulate the development of enzyme-altered hepatic foci was not unique to lead nitrate since the same phenomenon was observed when three other hepatomitogens, nafenopin, cyproterone acetate, and ethylene dibromide, were used. 相似文献
165.
166.
Gioacchino Calapai Maria C. Marciano Giuseppina Costantino Alessandra Russo Francesco Corica Lidia Sautebin Massimo Di Rosa Achille P. Caputi 《European journal of pharmacology》1998,360(2-3):147-154
Intracranial administration of
-arginine causes a reduction of the water intake induced by water deprivation or by intracerebroventricular (i.c.v.) injection of angiotensin II (angiotensin II), through the release of nitric oxide (NO) in the central nervous system. We studied the effects of i.c.v. angiotensin II (120 ng/rat) in association with i.c.v.
-arginine (2.5–10 μg/rat) on blood pressure. We also studied the effects of both peripheral and central angiotensin II injection (1.5–6 mg kg−1 i.p. and 30–120 ng rat−1 i.c.v., respectively) on NO synthase activity in the cortex, diencephalon and brainstem, after water deprivation (24 h), conditions producing activation of the renin-angiotensin system.
-arginine dose dependently antagonized the increase in blood pressure induced by i.c.v. angiotensin II (P<0.001). Peripheral administration of angiotensin II produced a dose-dependent reduction of NO synthase activity in the brainstem and cortex (P<0.001), but not in the diencephalon. Water deprivation produced similar effects on brain NO synthase activity. Angiotensin II i.c.v. injection caused NO synthase activity reduction in all brain regions studied (P<0.001). Our findings suggest that NO and angiotensin II could play opposite roles in brain regulation of blood pressure and drinking behaviour. 相似文献
167.
Giuseppina Ceccorulli Francesco Manescalchi 《Macromolecular chemistry and physics.》1973,168(1):303-313
Dilatometry and differential scanning calorimetry have been used to study the crystallization kinetics of poly[imino(1-oxooctamethylene)] (Nylon 8) over the temperature range of 182–190°C. The influence of molecular weight and nucleating agents on the kinetic parameters was investigated. Experimental data, analyzed by the AVRAMI equation: Θ = exp(-Ktn), gave values of n = 5 and 6. A mechanism of crystal growth according to a sheaf-like structure, accounted for by the theory for such values of n, has been supported by microscopic observations. 相似文献
168.
169.
170.
Caraglia M Marra M Budillon A Meo G Ricciardiello F Bismuto E Brachelente G Francini G Giordano A Correale P Abbruzzese A 《Cancer biology & therapy》2005,4(10):1159-1167
The multi-drug combination of oxaliplatin (OXA), 5-Fluorouracil (5-FU) and leucovorin (LF) is currently considered as the gold standard treatment for metastatic colorectal carcinoma. In previous studies, we have studied a chemotherapy regimen containing gemcitabine (GEM), OXA, LF, and 5-FU (named GOLF regimen) that has shown a good safety profile and highly significant anti-tumor activity. In the present study, we have investigated on the anti-tumour mechanisms of GOLF in human colon cancer HT-29 and WiDr cell lines. We have found that GOLF induced growth inhibition that was largely caused by apoptosis differently from other combinations. Moreover, the different drugs composing GOLF were highly synergistic in inducing growth inhibition. Apoptosis induced by GOLF combination was paralleled by PARP cleavage and caspase 9 and 3 activation that were not recorded in the other combinations. An about 85% decrease of the activity of Erk and Akt was found in GOLF-treated cells. These effects were likely due to decreased expression of the upstream activator Raf-1 and of Akt itself, respectively. The intracellular levels of these signalling components can be post-translationally regulated by ubiquitin-dependent degradation through proteasome. Therefore, we have evaluated the expression of some chaperone components and we have found that GOLF did not affect the expression of both heat shock protein (HSP) 90 and 27 but induced an about 90% increase of HSP70 levels suggesting the inactivation of the multi-chaperone complex. Moreover, an about 4-fold increase of the ubiquitination of Raf-1 was also found and the addition for 12 h of 10 microM proteasome inhibitor lactacystin caused an accumulation of the ubiquitinated isoforms of Raf-1. In conclusions, GOLF was a combination highly synergistic in inducing both growth inhibition and apoptosis of colon cancer cells. These effects likely occurred through the disruption of critical survival pathways and the inactivation of multi-chaperone complex. 相似文献