摘要:

This review focuses on the use of synthetic (non-viral) delivery systems for cancer gene therapy. Therapeutic strategies such as gene replacement/mutation correction, immune modulation and molecular therapy/‘suicide’ gene therapy type approaches potentially offer unique and novel ways of fighting cancer, some of which have already shown promise in early clinical trials. However, the specific and efficient delivery of the genetic material to remote tumors/metastases remains a challenge, which is being addressed using a variety of viral and non-viral systems. Each of these disparate systems has distinct advantages and disadvantages, which need to be taken into account when a specific therapeutic gene is being used. The review concentrates on particulate gene delivery systems, which are formed through non-covalent complexation of cationic carrier molecules (e.g. lipids or polymers) and the negatively charged plasmid DNA. Such systems tend to be comparatively less efficient than viral systems, but have the inherent advantage of flexibility and safety. The DNA-carrier complex acts as a protective package, and needs to be inert and stable while in circulation. Once the remote site has been reached the complex needs to efficiently transfect the targeted (tumor) cells. In order to improve overall transfection specificity and efficiency it is necessary to optimize intracellular trafficking of the DNA complex as well as the performance after systemic administration. Common principles and specific advantages or disadvantages of the individual synthetic gene delivery systems are discussed, and their interaction with tumor-specific and generic biological barriers are examined in order to identify potential strategies to overcome them

ISSN:0959-4973    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

2′ and 7 Polyol carbonates of paclitaxel were synthesized and screened as potential paclitaxel prodrugs. Paclitaxel is released from 7-(2′′,3′′-dihydroxypropylcarbonato) paclitaxel (Protaxel) at rates inversely proportional to pH, by an intramolecular cyclization. Compared to paclitaxel, maximum tolerated i.v. or i.p. doses (MTD) of Protaxel are about 2.5- to 3-fold higher; its efficacy is substantially higher in human cancer line xenografts in athymic mice, especially in prostate PC-3, breast MDA-MB 468 and ovary OVCAR-1.

ISSN:0959-4973    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Intravenous administration of paclitaxel is hindered by poor water solubility of the drug. Currently, paclitaxel is dissolved in a mixture of ethanol and Cremophor EL; however, this formulation (Taxol®) is associated with significant side effects, which are considered to be related to the pharmaceutical vehicle. A new polymer-conjugated derivative of paclitaxel, PNU166945, was investigated in a dose-finding phase I study to document toxicity and pharmacokinetics. A clinical phase I study was initiated in patients with refractory solid tumors. PNU16645 was administered as a 1-h infusion every 3 weeks at a starting dose of 80 mg/m2, as paclitaxel equivalents. Pharmacokinetics of polymer-bound and released paclitaxel were determined during the first course. Twelve patients in total were enrolled in the study. The highest dose level was 196 mg/m2, at which we did not observe any dose-limiting toxicities. Hematologic toxicity of PNU166945 was mild and dose independent. One patient developed a grade 3 neurotoxicity. A partial response was observed in one patient with advanced breast cancer. PNU166945 displayed a linear pharmacokinetic behavior for the bound fraction as well as for released paclitaxel. The study was discontinued prematurely due to severe neurotoxicity observed in additional rat studies. The presented phase I study with PNU166945, a water-soluble polymeric drug conjugate of paclitaxel, shows an alteration in pharmacokinetic behavior when paclitaxel is administered as a polymer-bound drug. Consequently, the safety profile may differ significantly from standard paclitaxel.

ISSN:0959-4973    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

c-raf-1, a cytoplasmic serine/threonine protein kinase, plays an important role in mitogen- and damage-responsive cellular signal transduction pathways. Expression of c-raf-1 modifies cell growth, proliferation and survival. Although expression of c-raf-1 has been studied in several tumors, the role of c-raf-1 in leukemia is so far unclear. We examined the expression of c-raf-1 in the human leukemia cell lines U937 and K562, and in a cytosine arabinoside (Ara-C)-resistant cell line (K562AC) derived from K562. Expression of c-raf-1 was increased in U937 and in Ara-C-resistant K562AC cells compared with the parental cells. We then investigated whether inhibition of c-raf-1 expression by antisense oligonucleotides increases the sensitivity to Ara-C in U937 and K562AC cells. Antisense oligonucleotides for c-raf-1 inhibited expression of c-raf-1 mRNA, but did not affect cell growth and increased sensitivity to Ara-C but not to other drugs such as adriamycin, VP-16 or vincristine. These results suggest that c-raf-1 is one of the factors involved in Ara-C resistance in leukemia and lend weight to the case for development of anti-cancer therapeutics involving oncogene-targeted antisense oligonucleotides.

ISSN:0959-4973    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

From July 1994 to December 1996, 41 patients with previously untreated, advanced bulky squamous cell carcinoma arising from the buccal mucosa (BSCC) were enrolled. All patients were males with a median age of 47 years (range 29-72). The tumor extent was stage III/IV: three of 38, T4: 85%, N2-3: 20%. Patients were initially scheduled to receive intra-arterial (i.a.) chemotherapy, followed by i.v. chemotherapy and regional therapy. The i.a. chemotherapy catheter was properly placed by external carotid artery angiography via the femoral artery. The i.a. chemotherapy consisted of cisplatin (P) 100 mg/m2day 1 plus 5-fluorouracil (F) 1000 mg/m2day 1-4, and the i.v. chemotherapy consisted of PF (10 patients) or PF plus methotrexate 200 mg/m2day 15 and 22 (31 patients). All chemotherapy regimens were administered at 4-week intervals. The response rate of i.a. plus i.v. chemotherapy for the primary site was 85% (35 of 41) with 29% complete remission (CR) (12 of 41). The response and CR rates of neck nodes were 82% (14 of 17) and 41% (seven of 17), respectively. The combined overall response rate was 80% (33 of 41) with a 29% CR (12 of 41). Major toxicity from i.a. chemotherapy of WHO grade ⩾3 included: mucositis of infusion area (76%), hemialopecia (56%) and leukopenia (5%). Three neurologic complications of i.a. chemotherapy including one hemiparesis occurred. The median follow-up time was 47 months (range 36-66 months), and the overall survival and disease-free survival were both 34% (14 of 41). Four patients were cured with chemotherapy alone and eight patients (19.5%) were cured without surgical intervention. Using i.a. chemotherapy as a cytoreductive therapy followed by subsequent i.v. chemotherapy produces a high response rate and an encouraging degree of complete response rate in advanced bulky BSCC. However, toxicity management and catheter placement will need to be improved in order to better define the role of this therapy in advanced BSCC.

ISSN:0959-4973    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

We have reported a 33% partial response rate with acceptable toxicity using weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (LV) in patients with far advanced biliary tract cancers (BTC). In this study, we added mitomycin (MMC) to 5-FU and LV in an attempt to improve the response rate and survival. From July 1997 to September 1999, 25 chemotherapy-naive patients with pathology-proven far advanced BTC and periampullar cancers were enrolled. The regimen consisted of MMC 10 mg/m2every 8 weeks combined with 5-FU 2600 mg/m2and LV 150 mg at a schedule of 24-h infusion weekly for 6 weeks followed by a 2 week break. There were 10 males and 15 females with a median age of 57 years (range 40-76). The sites of primary tumor were 15 intrahepatic cholangiocarcinomas (CC), one perihilar CCs, three distal BTC, three gallbladder cancers (GB) and three periampular cancers. A total of 148 sessions of chemotherapy were given with a mean of 8 (range 2-18). Nineteen patients were evaluable for response. The response rate was: 26% (five of 19) partial response, 42% (eight of 19) stable disease and 32% (six of 19) progressive disease. All of the patients were evaluable for toxicity. Toxicities more than grade III-IV were thrombocytopenia 16% (four of 25), leukopenia 12% (three of 25) and vomiting 4% (one of 25). There were four treatment-related deaths. The median time to disease progression was 3 months. The median survival was 6 months. A combination of MMC with weekly high-dose 5-FU and LV in patients with BTC did not improve the response rate, but produced more toxicity than weekly high-dose 5-FU and LV alone.

ISSN:0959-4973    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

In order to determine if age and comorbidity influence the tolerability of the cytoprotective agent amifostine, we compared side effects related to amifostine in patients ⩾70 years (group I) with patients <70 years (group II). We evaluated 268 consecutive administrations of amifostine (119 in group I and 149 in group II, respectively), given i.v. at a dose of 740 mg/m2just before platinum-, taxol- or cyclophosphamide-based chemotherapy. Transient hypotension was the most common side effect occurring in association with amifostine. Decreases in systolic blood pressure >20 mmHg were of similar frequency in both groups (27.1 versus 28.8% of amifostine infusions in group I and II, respectively). Hypotension did not result in medical sequelae in any of the patients. The amifostine infusion was interrupted 16 times in group I and 8 times in group II, respectively, mainly due to hypotension, but could be restarted after a few minutes in all patients except for three cases in group I. Patients in group II more often suffered from nausea/vomiting than in group II (20.8 versus 10.0% in group I). Other subjective symptoms (e.g. warmed, flushed sensation, sneezing, metallic taste, mouth dryness, dizziness and sleepiness) and hypocalcemia occurred with a similar frequency in both groups. Adverse effects associated with amifostine were not observed more frequently in elderly patients than in younger ones, although more elderly patients had a comorbidity than the younger ones.

ISSN:0959-4973    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The objective of this study was to define the minimally effective dose of cyclosporin A (CsA) that would result in a maximal increase of the systemic exposure to oral paclitaxel. Six evaluable patients participated in this randomized cross-over study in which they received at two occasions two doses of 90 mg/m2oral paclitaxel 7 h apart in combination with 10 or 5 mg/kg CsA. Dose reduction of CsA from 10 to 5 mg/kg resulted in a statistically significant decrease in the area under the plasma concentration-time curve (AUC) and time above the threshold concentrations of 0.1 μM (T>0.1 μM) of oral paclitaxel. The mean (±SD) AUC andT>0.1 μM values of oral paclitaxel with CsA 10 mg/kg were 4.29±0.88 μM·h and 12.0±2.1 h, respectively. With CsA 5 mg/kg these values were 2.75±0.63 μM·h and 7.0±2.1 h, respectively (p= 0.028 for both parameters). In conclusion, dose reduction of CsA from 10 to 5 mg/kg resulted in a significant decrease in the AUC andT>0.1 μM values of oral paclitaxel. Because CsA 10 mg/kg resulted in similar paclitaxel AUC andT>0.1 μM values compared to CsA 15 mg/kg (data which we have published previously), the minimally effective dose of CsA is determined at 10 mg/kg.

ISSN:0959-4973    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Inhibitors of topoisomerases are widely used in the treatment of cancer, including inhibitors of topoisomerase I (camptothecin analogs such as irinotecan and topotecan) and topoisomerase II (etoposide and doxorubicin). The novel bis-phenazine, XR5944, is a joint inhibitor of topoisomerase I and II as shown by the stabilization of topoisomerase-dependent cleavable complexes. XR5944 demonstrated exceptional activity against human and murine tumor cellsin vitroandin vivo. In a range of cell lines XR5944 (IC500.04-0.4 nM) was significantly more potent than TAS-103, originally proposed as a joint topoisomerase I and II inhibitor, as well as agents specific for topoisomerase I or II (topotecan, doxorubicin and etoposide). In addition, XR5944 was unaffected by atypical drug resistance and retained significant activity in cells overexpressing P-glycoprotein or multidrug resistance-associated protein. Antitumor efficacy of XR5944 was demonstrated in human carcinoma xenograft models (H69 small cell lung cancer and HT29 colon). In the HT29 model, which is relatively unresponsive to chemotherapy, XR5944 (15 mg/kg i.v., q4d×3) induced tumor regression in the majority of animals (six of eight), whereas TAS-103, dosed at its maximum tolerated dose (45 mg/kg i.v., q7d×3), only induced a delay in tumor growth compared with control animals. In the H69 model, low doses of XR5944 (5 mg/kg i.v., qd×5/week for 2 weeks or 10-15 mg/kg i.v., q4d×3), induced complete tumor regression in the majority of animals. In contrast, topotecan (20 mg/kg i.v., q4d×3) or etoposide (30 mg/kg i.v., q5d×5) only slowed the tumor growth rate. These studies show that XR5944 is a highly active novel anticancer agent that is well tolerated at efficacious doses.

ISSN:0959-4973    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

We present experimental data which establish the organometallic compounds vanadocene dichloride (VDC) and vanadocene acetylacetonate (VDacac) as potent anti-proliferative agents. We first examined the effects of VDC and VDacac on the rapid embryonic cell division and development of Zebrafish. Both compounds were capable of causing cell division block at the 8-16 cell stage of embryonic development followed by total cell fusion and developmental arrest. We next examined the effect of VDC and VDacac on proliferation of human breast cancer and glioblastoma cell lines using MTT assays. VDC inhibited the proliferation of the breast cancer cell line BT-20 as well as the glioblastoma cell line U373 in a concentration-dependent fashion with IC50values of 11.0, 14.9 and 18.6 μM, respectively. VDacac inhibited cellular proliferation with IC50values of 9.1, 26.9 and 35.5 μM, respectively. Whereas in vehicle-treated control cancer cells mitotic spindles were organized as a bipolar microtubule array and the DNA was organized on a metaphase plate, vanadocene-treated cancer cells had aberrant monopolar mitotic structures where microtubules were detected only on one side of the chromosomes and the chromosomes were arranged in a circular pattern. In contrast to control cells which showed a single focus of γ-tubulin at each pole of the bipolar mitotic spindle, VDC- or VDacac-treated cells had two foci of γ-tubulin on the same side of the chromosomes resulting in a broad centrosome at one pole. All monopolar spindles examined had two foci of γ-tubulin labeling consistent with a mechanism in which the centrosomes duplicate but do not separate properly to form a bipolar spindle. These results provide unprecedented evidence that organometallic compounds can block cell division in human cancer cells by disrupting bipolar spindle formation. In accordance with these results vanadocene treatment caused an arrest at the G2/M phase of the cell cycle. This unique mechanism of anti-mitotic function warrants further development of vanadocene complexes as anti-cancer drugs.

ISSN:0959-4973    

出版商:OVID    

年代:2001

数据来源: OVID