摘要:

IDN 5390 is aseco-derivative cytostatic taxane. Originally selected for its ability to affect endothelial cell motility, the anti-angiogenic properties of IDN 5390 have been documented in experimental models,in vivoandin vitro. Preclinical studies indicate that,in vivo, oral IDN 5390 has a favorable bioavailability, is well tolerated and shows a significant anti-neoplastic activity on a panel of different tumor models, including paclitaxel-resistant tumors. According to its cytostatic rather than cytotoxic nature, frequent administrations of non-toxic doses have proven to be the optimal schedule for IDN 5390 treatment. Preliminary findings suggest the use of this compound in combination with conventional anti-neoplastic therapy. IDN 5390 can be considered the prototype of a new class of well-tolerated, orally available anti-angiogenic taxane derivatives with cytostatic properties.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Pegylation of a protein can improve not only its formulation properties, but also both its pharmacokinetic and pharmacodynamic performance. Pegfilgrastim was made by linking a 20-kDa polyethylene glycol molecule to filgrastim, producing a long-acting cytokine requiring less frequent dosing than its parent drug. This review describes the clinical development of pegfilgrastim, and discusses its potential benefits to patients and caregivers in the prophylaxis of chemotherapy-induced neutropenia. Pegfilgrastim has a longer half-life and slower elimination rate than filgrastim, resulting in an increased serum concentration over time. Serum levels of pegfilgrastim are maintained until after a chemotherapy-induced neutrophil nadir and then decline rapidly as the neutrophil count recovers, consistent with a neutrophil-mediated clearance mechanism. In two pivotal phase III studies of women receiving chemotherapy for breast cancer, a single injection of pegfilgrastim per chemotherapy cycle, dosed either by body weight (100 μg/kg) or as a fixed dose (6 mg), was comparable to daily filgrastim (5 μg/kg) for all efficacy parameters, including duration of severe neutropenia and depth of neutrophil nadir. Analysis of pooled data from these studies showed a significantly lower incidence of febrile neutropenia in patients receiving pegfilgrastim compared with filgrastim (11 versus 19%,p<0.05), and a trend towards a lower risk of hospitalization and use of i.v. anti-infectives. The safety profiles of pegfilgrastim and filgrastim were similar. Pegfilgrastim given once per chemotherapy cycle is as effective and well tolerated as daily injections of filgrastim. With its more convenient dosing regimen, pegfilgrastim has the potential to improve quality of life and compliance in patients, and to be more cost effective.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Hormonal agents have a confirmed role in the management of postmenopausal women with receptor-positive advanced breast cancer. Until recently, tamoxifen has been the accepted agent for treating these patients. However, accumulating evidence suggests that the new antiaromatase agents will replace the antiestrogens as the preferable option in hormone-naive patients. Comparative trials indicate that the aromatase inhibitors, anastrozole and letrozole, and the aromatase inactivator, exemestane, have at least equivalent efficacy to tamoxifen with similar or superior tolerability. These agents are also more effective than the progestin, megestrol acetate, when studied in patients progressing on tamoxifen. The improved aromatase selectivity and high potency of these antiaromatase agents when compared with earlier agents have resulted in improved efficacy and tolerability. Additionally, no cross-resistance has been reported between the antiaromatase agents and tamoxifen or, in some instances, among the antiaromatase agents themselves. The role of antiaromatase agents will certainly expand in the near future to include not only treatment of metastatic breast cancer, but use in the adjuvant and neoadjuvant settings as well, and, ultimately, breast cancer prevention. The results of ongoing investigations are awaited with interest.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

AMD473 (ZD0473;cis-amminedichloro[2-methylpyridine]platinum [II]) is a new generation anticancer agent that, in preclinical studies, shows evidence of an extended spectrum of antitumor activity and overcomes platinum resistance mechanisms. Here we evaluate the activity of AMD473 (ZD0473) in a panel of 120 human tumor specimens using a soft agar cloning assay (human tumor colony-forming assay). When tumor cells were treated with 1.0, 4.0 or 16.0 μg/ml AMD473 (ZD0473) for 2 h,in vitroresponses were observed in 18% (9/51), 33% (17/51) and 44% (19/43) of assessable specimens. Treatment of tumor cells with the same concentrations of AMD473 (ZD0473) for 24 h resulted in responses of 33% (16/48), 63% (30/48) and 85% (35/41). AMD473 (ZD0473) (16 μg/ml; 24 h) demonstrated activity towards 100% of the non-small cell lung (5/5) and ovarian (8/8) cancer specimens and 73% (8/11) of the breast cancer specimens treated. Low levels of cross-resistance to cisplatin cyclophosphamide, 5-flurouracil, etoposide and gemcitabine were observed. There was a positive relationship between AMD473 (ZD0473) concentration and effect, and a significant difference between response to 2- versus 24-h exposure to 4 or 16 μg/ml (p=0.003 andp=0.001, respectively). These responses demonstrate efficacy at pharmacologically relevant concentrations, suggesting AMD473 (ZD0473) deserves further evaluation.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Caveolin 1 expression is down-regulated in various cancer cell lines. Interestingly, in several drug-resistant cancer cells, a strong induction of caveolin 1 expression has been reported, suggesting a role for caveolin 1 in the acquisition and/or the maintenance of the multidrug-resistance phenotype. Here, we show, in drug-sensitive lung cancer cells (A549, Calu-6 or NCI-H69), that exposure to cytotoxic drugs (taxol, doxorubicin or etoposide) is sufficient to strongly up-regulate caveolin 1 and 2 protein levels. This up-regulation is sustained even 1 week after drug removal. Our results suggest that caveolin up-regulation is an early cellular response to a cytotoxic stress taking place before drug resistance.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Virulizin is a novel biological response modifier (BRM) approved for the treatment of melanoma and is currently in a phase III clinical trial against advanced pancreatic cancer. The purpose of this study was to define the anti-cancer activity of Virulizin against a number of solid human tumors. The therapeutic effect of Virulizin was evaluated in mouse xenograft models, and the results demonstrate that Virulizin has high efficacy against breast, ovarian and prostate tumor xenografts. Seventy-seven percent inhibition, with an optimal T/C value of 24.8%, was observed in human beast MDA-MB-231 xenografts treated with Virulizin as compared to saline-treated controls (p=0.0004). In human ovarian SK-OV-3 tumor xenografts, administration of Virulizin inhibited tumor growth by 77.6% compared to saline controls (p=0.0439). Furthermore, high anti-tumor activity was also demonstrated in DU145 and PC-3 prostate tumor xenografts, as indicated by 72.6 and 49.1% suppression of tumor growth (versus saline controls,p=0.0007 orp=0.0049), respectively. Direct comparisons with the anti-tumor activities of conventional drugs demonstrated that Virulizin has higher or equal efficacy against all four tumors tested. Finally, addition of Virulizin into co-cultures of tumor cells and macrophages stimulated the cytolytic activity of the macrophages against the tumor cells in a dose-dependent manner. This result suggests that stimulation of immune cells is at least part of the anti-tumor mechanism of action of Virulizin. These results clearly demonstrate that Virulizin inhibits the growth of human breast, ovarian and prostate tumors, indicating great potential for expansion of the clinical indications for this novel BRM.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The annual incidence of malignant melanoma is estimated at 10–12 per 100 000 inhabitants in countries of Central Europe and the US, with more recent estimates showing a dramatic upward trend. Taurolidine (Carter/Wallace, Cranberry, NJ) is a novel, potentially effective, antitumor chemotherapeutic agent. We hypothesized that Taurolidine could inhibit the growth, induce apoptosis, affect the cell cycle and change morphology of melanoma cells. We expected this process to be different in adherent and floating subpopulations that may be reflective of solid tumors and their metastases. Analysis of MNT-1 human and B16F10 murine melanoma cells showed that at 72 h the IC50of Taurolidine was 25.4±3.3 μM for MNT-1 human melanoma cells and 30.9±3.6 μM for B16F10 murine melanoma cells. Taurolidine induced DNA fragmentation of melanoma cells in a dose-dependent manner. Taurolidine (75 and 100 μM) induced 52–97% Annexin-V binding (apoptosis), respectively. Evaluation of cell cycle after 72 h exposure to Taurolidine (0–100 μM) revealed that the percentage of melanoma cells in S phase increased from 27 to 40% in the adherent subpopulation and from 33 to 49% in the floating subpopulation. Phase contrast microscopy revealed a marked swelling of melanoma cells and decreasing cell numbers in adherent subpopulation starting at 24 h with 25 μM Taurolidine. Shrinkage of cells dominated at 75–100 μM Taurolidine. Using Cytospin assay in the floating population, we observed swelling of melanoma cells induced by 25–100 μM Taurolidine and appearance of giant (multinuclear) forms resulting from exposure to 75–100 μM Taurolidine. Some floating cells with normal morphology were observed with low concentrations of Taurolidine (0–25 μM). These data show that effects of Taurolidine may be different in adherent and floating subpopulations of melanoma cells. More importantly, floating subpopulations that may contain some viable melanoma cells, may be reflective of potential metastasis after treatment of solid tumorsin vivo.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The aim of this study was to assess survival and prognostic factors of 98 consecutive patients with unresectable glioblastoma multiforme (GBM) after stereotactic biopsy. Patients were diagnosed between 1993 and 1998, and the treatment modality subsequent to stereotactic biopsy was determined by the year of diagnosis. Before 1995, patients did not receive further specific therapy after stereotactic biopsy (n=36). In 1996, patients were administered radiotherapy starting within 6 weeks after stereotactic biopsy (n=24). From 1997 to 1998, patients received combined radio-/chemotherapy (RCT; CCNU orally) starting within 2 weeks after stereotactic biopsy (n=38). Patients' age ranged from 21 to 84 (median 64) years and their median Karnofsky performance score 2 weeks after stereotactic biopsy was 80 (range 60–100). Survival and prognostic factors were analyzed with respect to administered treatment modalities (without specific therapy versus radiotherapy versus combined RCT), with respect to age (>/≤50 years), gender, Karnofsky performance score (≥/<80), tumor location (frontal, parieto-temporal, central, occipital) and tumor size (>/≤5 cm; tumor multiplicity was considered as diameter >5 cm) by the Kaplan–Meier method, by log-rank test and multivariate Cox regression analysis. Post-biopsy treatment modality was the strongest predictor for survival. Median (range) survival was 9 (3–47) weeks in those without specific therapy, 13 (5–54) weeks in patients receiving radiotherapy and 31 (11–101) weeks in patients receiving combined RCT (p≤0.001). Age≤50 years (p≤0.05) in addition to tumor size in multivariate Cox analysis were found to be of significant influence onto survival, too. Combined RCT could be performed on a complete outpatient basis. Toxicity consisted of mild asymptomatic thrombocytopenia. We conclude that the administration of combined RCT within a minimum interval after stereotactic biopsy yielded a significant increase in survival. Patients' acceptance was excellent. These results encourage us to treat even patients with unresectable GBM with combined RCT.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The expression of receptor tyrosine kinase c-kitand its biologic significance in pancreatic cancer are unclear. We studied the expression of c-kitprotein (c-KIT) in resectable invasive ductal carcinomas (IDCs) of the pancreas, in order to assess whether a selective c-kitinhibitor, STI571 (Glivec), may be applied for the treatment of pancreatic IDCs. This study included 72 pancreatic IDC patients who received a pancreatectomy between 1982 and 2002. The expression of c-KIT was analyzed retrospectively by immunohistochemistry. c-KIT was expressed in 78% (56/72) of the pancreatic IDCs. c-KIT expression did not correlate with any clinicopathological factor of pancreatic IDC and c-KIT expression had no significant influence on the survival of the patients. The survival rate of the adjuvant chemotherapy (ACT) (+) group was significantly higher than that of the ACT (−) group, but c-KIT expression had no significant effects on the efficacy of the ACT. Multivariate analysis indicated that the pTNM stage, grade and ACT were all significant variables for survival in IDCs overall. As c-KIT was expressed in 78% of the pancreatic IDCs, it suggests that STI571 may be a beneficial agent for chemotherapy against human pancreatic IDCs.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Our objective was to evaluate the role of amifostine as a cytoprotector in patients with solid tumors receiving the myelosuppressive regimen of gemcitabine/cisplatin combination. Patients with advanced solid tumors were randomized to gemcitabine–amifostine–cisplatin (GAP) or gemcitabine–cisplatin (GP) in Cycle 1 (C1) and then were crossed over to the other treatment in Cycle 2 (C2). Amifostine at 740 mg/m2, followed by gemcitabine and cisplatin, were given for 2 consecutive weeks, every 4 weeks. Two GP combinations were studied: G 1000 mg/m2and P 40 mg/m2days 1, 8 (high dose), and G 800 mg/m2and P 30 mg/m2days 1, 8 (low dose). Forty patients were enrolled. Of the 19 patients treated with high-dose GP, 11 (nine patients GP in C1 and GAP in C2, two patients GAP in C1 and GP in C2) completed 2 cycles of therapy. Of the eight non-evaluable patients, five patients dropped out due to toxicity or refusal after treatment with amifostine in C1. Of the 21 patients treated with low-dose GP, 15 (eight patients GP in C1 and GAP in C2, seven patients GAP in C1 and GP in C2) were likewise evaluable. The incidence of grade 3 or 4 hematologic toxicities was similar for GP and GAP during the first 2 cycles of treatment, and there were no statistically significant differences in mean absolute neutrophil count, hemoglobin level and platelet levels between the cycles in each arm. We conclude that amifostine, at 740 mg/m2, does not lead to less myelosuppression when combined with gemcitabine/cisplatin chemotherapy regimens and may possibly contribute to subjective intolerance.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID