摘要:

Yondelis®(trabectedin, ET-743) is a novel antitumor agent derived from a marine source, the Caribbean tunicateEcteinascidia turbinata. Preclinical studies demonstrated activity at low concentrations against a variety of tumors. The mechanism by which ET-743 exerts its antitumor activity has not been completely elucidated yet. Binding to the minor groove of DNA which causes a bend towards the major groove has been demonstrated. Furthermore, ET-743 interferes with DNA binding proteins and transcription factors. Clinical studies have been initiated as phase I dose-finding studies at four different treatment regimens. Dose-limiting toxicities were hematological, including neutropenia and thrombocytopenia. Furthermore, significant liver toxicity was observed, especially as a rise in transaminase levels. Antitumor activity in phase I and phase II trials was studied in multiple tumor types, including soft tissue sarcomas, melanomas and breast cancer. ET-743 is currently being extensively investigated in advanced soft tissue sarcomas. The present review describes the development of ET-743, highlighting chemical properties, mode of action, metabolism and preclinical and clinical studies.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Synthetic triptycene analogs (TT code number) mimic the antitumor effects of daunorubicin in the nanomolar rangein vitro, but have the advantage of blocking nucleoside transport and retaining their efficacy in multidrug-resistant (MDR) tumor cells. Since TT bisquinones induce poly(ADP-ribose) polymerase-1 cleavage at 6 h and internucleosomal DNA fragmentation at 24 h, which are, respectively, early and late markers of apoptosis, these lead antitumor drugs were tested for their ability to trigger the DNA topoisomerase (Topo) inhibitions responsible for the initial and massive high-molecular-weight cleavage of DNA required for tumor cells to commit apoptosis. Interestingly, antitumor TTs have the unusual ability to inhibit, in a concentration-dependent manner, the relaxation of supercoiled plasmid DNA catalyzed by both purified human Topo I and II enzymes. However, if there is a relationship between the ability of TT analogs to inhibit Topo activities and their quinone functionality and cytotoxicity, it is far from perfect, suggesting that other molecular targets may be involved in the mechanism of action of these antitumor drugs. Moreover, one of the most cytotoxic TT bisquinone, 6-bromo-7-methoxy- or 7-bromo-6-methoxy-2-N-methylamino-1 H,4 H,5 H,8H-9,10-dihydro-9,10-[1′,2′]benzenoanthracene-1,4,5,8-tetraone (TT24), inhibits Topo II activity more effectively than amsacrine (m-AMSA) and matches the Topo I inhibitory effect of camptothecin (CPT). The dual inhibitory activity of TT24 is substantiated by the findings that TT24 mimics the action ofm-AMSA in the Topo II assay, where the Topo I inhibitor CPT is ineffective, and also mimics the action of CPT in the Topo I assay, where the Topo II inhibitor etoposide is ineffective. Because of their ability to target nucleoside transport and topoisomerase activities, synthetic TT bisquinones might represent a novel class of bifunctional drugs valuable to develop new means of polychemotherapy and circumvent MDR.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

It is well established that certain chemotherapeutic agents have potent antiangiogenic properties which may be part of their antitumor activity. Temozolomide (TMZ) is a lipophilic methylating agent used in the therapy of malignant melanoma and other tumors. We sought to determine whether TMZ is capable of inhibiting angiogenesis or influencing endothelial function. We used thein vivochorioallantoic membrane (CAM) assay, and HUVEC-basedin vitroMatrigel, adhesion and proliferation assays to determine the antiangiogenic effects of different doses of TMZ. In the CAM assay, angiogenesis was significantly inhibited by 5 μM TMZ, a concentration also found to be effective in interfering within vitroangiogenesis as measured by the Matrigel assay. For the inhibition of basic fibroblast growth factor (bFGF)-, vascular endothelial growth factor (VEGF)- or &bgr;-phorbol 12-myristate-13-acetate (PMA)-induced endothelial cell proliferation or endothelial cell adhesion to fibronectin, TMZ concentrations of at least 25 μM were necessary, indicating that bFGF-, VEGF- or protein kinase C-mediated pathways may not primarily be involved in the observed antiangiogenic effect. Thus, we could demonstrate that TMZ inhibits angiogenesis at low, non-toxic doses that correspond to the plasma concentrations achieved by an oral application of 20 mg/m2every 8 h. This ‘metronomic’ scheduling has already been used in phase I studies and has produced antitumor effects. Therefore, the antitumor activity of TMZ may, at least in part, be due to its antiangiogenic properties. The precise mechanism of its antiangiogenic action remains to be elucidated.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Small cell lung cancer (SCLC) responds to treatment with cisplatin and etoposide, but relapse is rapid and survival rates are low. Our aims were to determine the mechanisms of resistance and the potential for paclitaxel (Taxol) to overcome any drug or radiation resistance. To mimic clinical treatment, H69 SCLC cells, representative of the classic form of the disease, and H82 cells, with the phenotype of the more resistant variant disease, were treated intermittently with 100 ng/ml cisplatin or 500 ng/ml etoposide (approximate IC50drug doses) to produce stable sublines. Drug and radiation resistance were determined using the MTT assay. Protein expression was determined by Western blot. The effect of paclitaxel on drug resistance was determined by cytotoxicity assays. Intermittent 4-day treatment with 100 ng/ml cisplatin caused 2- to 3-fold resistance to cisplatin (n=5;p<0.05), and 2- to 5-fold cross resistance to etoposide, alkylating drugs, the Vinca drugs and radiation. Resistance was mediated primarily by changes in glutathione metabolism and was not associated with changes in MRP2 transport protein. Treatment with etoposide (500 ng/ml) produced cells with 2-fold resistance to etoposide (n=5;p<0.05). Cross-resistance was limited and mediated by decreased topoisomerase II&agr;. Treatment of both drug-resistant sublines with a maximal non-cytotoxic dose of paclitaxel sensitized them to other drugs and to radiation, although this treatment had no effect on the parental H69 or H82 cells. We conclude that paclitaxel may play an important role in the treatment of refractory SCLC.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Raltitrexed (Tomudex®; TOM) hepatotoxicity is usually characterized by a transient and self-limiting increase in transaminase levels. How this may condition daily clinical practice is still unclear. The aim of this study was to investigate predictive factors of TOM hepatotoxicity. In total, 130 patients were treated at two medical oncology institutions with TOM (3 mg/m2) (52 patients) or TOM plus oxaliplatin (TOMOX) (100 mg/m2day 1 or 70 mg/m2day 1, 8) (78 patients). A multinomial logistic regression (adjusted for multilevel data) was performed (on all administered chemotherapy courses) to assess the dependence of hepatic toxicity on a set of clinical factors correlated with patient, disease and treatment characteristics. Creatinine clearance was calculated by the Cockcroft formula before each chemotherapy course. Most of the patients presented colorectal cancer (95%) and metastatic disease (93%). Out of the 130 patients, 41 were aged 70 or more, while 119 (91.5%) had a good performance status (PS) (ECOG 0 or 1). Before chemotherapy, liver metastases were present in 78 (60%) patients and elevated transaminase in 25 (19%). A total of 584 courses were administered (252 TOM and 332 TOMOX). National Cancer Institute Common Toxicity Criteria grade 1/2 and 3/4 transaminase toxicity was observed in 62 and 20% of patients, respectively. To control transaminase increase, glutathione (GSH) or ademethionine (SAMe) was administered in 96 and 129 cycles, respectively. Hepatotoxicity conditioned delays (a week or more) in 60 (10%) chemotherapy cycles and was the reason for the discontinuation of chemotherapy in eight (6%) patients. Among the factors evaluated with multivariate analysis, sex, age, PS, creatinine clearance, previous chemotherapy treatment, presence of liver metastases and oncology centre were not significantly associated with TOM hepatotoxicity. Elevated baseline transaminase levels (p = 0.001), number of chemotherapy cycles (p<0.001), TOM cumulative dose (p = 0.018), unprolonged intervals between courses (p<0.001) and TOMOX regimen (p<0.001) emerged as factors predictive of hepatotoxicity. In the same analysis, GSH (p<0.001) and SAMe (p<0.001) were hepatoprotective agents. This study confirmed TOM-based hepatotoxicity as a clinical relevant side-effect and a major factor for treatment delays or discontinuation. Predictive and protective factors listed above could assist the management of this toxicity that has probably been underestimated until now.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

We carried out a single-center series with the combination of irinotecan (CPT-11) plus protracted 5-fluorouracil (5-FU) infusion as second-line chemotherapy for patients previously treated with a single-agent fluoropyrimidine as monotherapy or in combination with oxaliplatin. Twenty-five patients diagnosed with advanced colorectal cancer (CRC) received CPT-11 300 mg/m2every 3 weeks plus 5-FU 250 mg/m2/day as a protracted infusion. Results were as follows. Twenty-four of 25 patients were evaluable for response. Two patients achieved a complete response and five a partial response, resulting in an overall response rate of 28%. Disease stabilization was obtained in 10 patients (40%), resulting in a tumor growth control rate of 68% (17 patients) and disease progression in seven (28%). Median progression-free interval was 6 months and median overall survival was 12 months. Neutropenia and diarrhea appeared as the most frequent adverse events, being grade 3/4 in 12 and 16% of patients, respectively. Mucositis, emesis, and hand and foot syndrome were mild. We conclude that protracted 5-FU infusion plus CPT-11 is an active and safe regimen for patients with advanced CRC. A phase III trial comparing this schedule with conventional CPT-11 monotherapy is warranted.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Oxaliplatin showsin vitroandin vivosynergism with 5-fluorouracil (5-FU). In this study we evaluate the clinical efficacy of oxaliplatin and 5-FU in heavily pretreated metastatic breast cancer. Eligible patients had to be pretreated with both anthracyclines and taxanes. Pretreatment with capecitabine was recommended but not mandatory. Chemotherapy: oxaliplatin 85 mg/m2/2 h day 1, folinic acid 400 mg/m2/2 h day 1, 5-FU 400 mg/m2i.v. push day 1, 5-FU 2400 mg/m2continuous infusion/48 h day 1, q2w. Fourteen patients were included: one male and 13 females; age: median 53 years (38–62); ECOG 0: three patients, 1: nine patients, 2: two patients; all patients were pretreated with anthracyclines and taxanes, capecitabine: nine patients, vinorelbine: six patients, trastuzumab: four patients, hormonal therapy: 12 patients; lines of prior palliative chemotherapy: 0: one patient, 1: three patients, 2: one patient, 3: three patients, 4: four patients, 5: two patients. Results: median number of cycles: 8 (range 1–17). Toxicity (14 patients evaluable; no. of patients with Common Toxicity Criteria grade 3/4): asthenia: 2/–, paraesthesia 3/–, leuko/neutropenia: 1/2, no neutropenic fever, other (alopecia, skin): 2/–. Response (12 patients evaluable, all with bidimensionally measurable disease): complete remission: no patients, partial remission: four patients (33%, all confirmed), stable disease: five patients, progressive disease: three patients. We conclude that despite the small number of patients, the combination of 5-FU and oxaliplatin shows promising efficacy in this heavily pretreated population.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The goal of our study was to determine whether an apoptosis assay used after short-term drug exposure could predict selective toxicity to cancer cells. To this end we compared the effect of eight anticancer drugs and 10 toxic compounds without known antitumor activity in cultures of human breast cancer cells and normal diploid fibroblasts by Apoptosis ELISA and growth inhibition assays. There was an overlap in concentration values of drugs and toxins inhibiting proliferation in cancer cells. In contrast, Apoptosis ELISA clearly distinguished between the two groups of compounds. Anticancer drugs induced apoptosis in cancer cells at 0.0015–0.5 μM, while toxins were effective at much higher concentrations of 8.0–50.0 μM. Moreover, six out of the 10 toxins did not induce apoptosis in cancer cells. The normal:cancer cell (N:C) ratio for growth inhibiting concentrations was in a similar range for anticancer drugs and toxins. The N:C ratio for apoptosis inducing concentrations was 33–200 for anticancer drugs and 1.3–3.0 for toxins. Our data indicate that apoptosis assays could be used to detect selective toxicity of anticancer drugs by determining apoptosis induction in cancer cells or through a comparison of apoptosis-inducing concentrations in normal and cancer cells.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

5-Fluorouracil (5-FU) has been used for more than 40 years in the treatment of neoplastic disease, and remains the standard first-line treatment for colorectal cancer in combination with irinotecan and leucovorin. Previous studies indicated that measurement of dihydropyrimidine dehydrogenase (DPD) gene expression before treatment was valuable in determining the potential benefit of and toxicity to 5-FU treatment. In this study, we investigated the association between intratumoral DPD gene expression and the adjacent normal tissue DPD gene expression and DPD mRNA expression level in non-paired colon tumor and normal colon tissue specimens. In addition, we have compared the difference of DPD gene expression at three different RNA concentrations from the same specimen (180, 100 and 5 ng/reaction, respectively). DPD expression was measured by quantitative RT-PCR using a LightCycler instrument in a total of 31 specimens. Gene expression values were expressed as a ratio of target gene (DPD) to the internal reference gene (G6PDH). Our study revealed no statistically significant difference (p=0.23) between tumor tissues and matched normal tissue in DPD expression. In contrast, the data on DPD mRNA expression in non-paired colon tumor and normal tissue specimens revealed a significant difference (p=0.0004) between the tumor group and the normal group. In the three RNA concentration groups, there was no significant difference (p=0.55) in gene expression at the different RNA concentrations from the same donor. These results demonstrate that intratumoral gene expression levels of DPD do not correlate with tumor cell percentage or with RNA concentration. Thus, DPD mRNA expression appears to be a valid sensitivity test for 5-FU in spite of a varying density of tumor cells and RNA yield in specimens submitted for analysis.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Human DU-145 prostate and MCF-7 breast tumor cell lines were stably transfected with plasmid pcDNA3.1-Luc expressing firefly luciferase. Studies were performed with the transfected cell lines to evaluate luminescent imaging for measuring the efficacy of anti-cancer agents.In vitroexperiments demonstrated a dose response of both cell lines to topotecan (Hycamtin®) with an IC50of 0.013 μM for MCF-7 Luc cells and 0.002 μM for DU-145 Luc cells.In vivoimaging experiments were performed using athymic nude mice inoculated i.p. with 5×106MCF-7 cells or s.c. with 5×106DU-145 cells and then treated with topotecan at 2.5 mg/kg body weight. Tumor progression and regression were monitored for 27 days. Animals inoculated s.c. with DU-145 Luc cells and then treated with topotecan demonstrated significant tumor growth and regression as measured with calipers and luminescent imaging. High correlation was observed between caliper and imaging results. The correlation coefficient was 0.75 for the control untreated group and 0.93 for the topotecan-treated group. Similarly, tumor progression and regression were measurable using luminescent imaging for untreated and topotecan-treated mice inoculated i.p. with MCF-7 Luc cells. These data indicate that luminescent imaging is a useful tool for evaluating anti-cancer drugsin vivoand may prove to be particularly useful for the development of novel agents. Luminescent imaging could also be used to locate and harvest residual tumors in drug-treated animals in order to study mechanisms of drug resistance.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID