摘要:

Tissue electroporation has been explored to enhance the local delivery of chemotherapueutic agents to solid tumors. The technique, known as electrochemotherapy (ECT), uses high-voltage pulses to deliver drugs across cancerous tissues. ECT has been demonstrated to be an effective treatment for cutaneous malignancies. Recent studies also indicate that the applications of ECT can be extended from the treatment of cutaneous cancers to the treatment of tumors of vital organs such as brain, liver, lungs and others. This review also discusses electrogene antitumor therapy.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

After oral or parenteral administration of chemotherapeutic agents, these drugs are transported to the tissues by the blood in different fractions: plasma water, plasma proteins or cells. In this review, the role of the red blood cell in storage, transport and metabolism of different anti-cancer drugs is described.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

In this phase II study, the efficacy and tolerability of gemcitabine were studied in 42 patients with locally advanced or metastatic breast cancer who had received up to one prior chemotherapy regimen in an adjuvant setting. Ten patients had received adjuvant chemotherapy. Twenty-eight patients (67%) had visceral disease spread at entry. Gemcitabine (1000 mg/m2) was administered weekly on days 1,8 and 15 of a 28-day cycle. The mean number of completed cycles was 3.9 and the mean dose delivered was 942.2 mg/m2. Ninety-seven percent of injections were administered as assigned. No complete responses were observed, but there were six partial responses and 24 patients with stable disease lasting 2–9 months. The overall response rate was 14.3% (95% Cl 5.4–28.5%). The median survival for all patients was 15.2 months. Maximum WHO grade 3 and 4 toxicities were observed in five patients for nausea and vomiting, one patient for diarrhea, one patient for pain, seven patients for alanine transaminase, and eight patients for segmented neutrophils. There were no grade 3 and 4 toxicities for alopecia. These data confirm modest single-agent gemcitabine activity in advanced or metastatic breast cancer. Gemcitabine's favorable toxicity profile makes it an ideal candidate for combination chemotherapy.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The intracellular localization of 14 structurally unique azonafide analogs was studied to determine if intracellular drug distribution is the limiting factor in azonafide cytotoxicity. Using scanning laser confocal microscopy, cytotoxicity of the azonafide analogs studies was observed in Chinese hamster ovary cells immediately after a 1 h exposure. The intracellular drug distribution patterns varied significantly for different analogs. Eight analogs showed primarily nuclear localization, five analogs showed primarily cytoplasmic localization and two analogs displayed perinuclear localization. In general, the type of chemical substitution on the anthracene nucleus determined the distribution pattern. For example, for each analog seven of eight nuclear-localizing analogs were amine-substituted agents, while four of five cytoplasmic-localized agents were ethoxy-substituted analogs. The individual exception within these groups was the 6-[(dimethylamino)ethoxy] agent that was nuclear localized. The two perinuclear-localized agents included the unsubstituted parent, azonafide, and its 6-methyl azonafide analog. Comparison of the cytotoxicity of the azonafides, based on intracellular localization, revealed that none of the localization patterns were associated with increased cytotoxicity. These results show that minor structural changes in the azonafide class of antitumor agents involving substitution along an anthracene chromophore result in substantially different intracellular drug distribution patterns. However, these distribution differences do not determine relative cytotoxic potencyin vitro.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Here we report that 2-deoxyglucose/Na azide treatment and free/conjugated doxorubicin are synergistic in cell killing. As demonstrated by fluorescence confocal microscopy, KB-V1 cells retained more conjugated doxorubicin than free doxorubicin. Verapamil or 2-deoxyglucose/Na azide enhanced only the retention of the free drug and the small (<70 kDa) conjugates, indicating that P-glycoprotein (P-gp) is not effective against large conjugates. Conjugated doxorubicin was excluded from nuclei. Initially both free and conjugated doxorubicin accumulated in cytoplasmic organelles. Upon 2-deoxyglucose/Na azide treatment, fluorescence labeling of organelles dissipated. Prolonged (24 h) incubation of conjugate-preloaded cells resulted in redistribution of some of the organelle-associated fluorescence to nuclei, suggesting decoupling. The appearance of free doxorubicin was confirmed by capillary electrophoresis. 2-Deoxyglucose/Na azide treatment also retarded decoupling. Our results suggest that energy starvation, in addition to increasing cellular retention of P-gp substrates, may affect cellular fate of conjugated drugs with a possible enhancing effect in cancer cell killing.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The activity of temozolomide, which has shown clinical activity against malignant glioma, has been assessedin vitroagainst short-term cultures derived from these tumors using an intermediate duration microtitration assay with MTT reduction as the end-point This assay has previously been shown to correlate closely with a monolayer clonogenic assay. Sensitivity was assessed in 15 short-term cultures (passage levels 3–9) derived from WHO grade III and IV astrocytomas. These cultures had a median ID50value of 258 μM for temozolomide and 16.13 μM for CCNU. Maximum serum concentrations of temozolomide are of the order of 75 μM but only three of 15 (20%) cultures had ID50S below this value. Fourteen of 15 (93%) cultures displayed cross-resistance between temozolomide and CCNU, although one line which was extremely resistant to CCNU retained sensitivity to temozolomide. Comparative studies of published clonogenic survival curves indicate that the short-term glioma cell lines used in this study have similar sensitivities to established glioma cell lines, whilst colon carcinoma cell lines and bladder carcinoma are often more resistant to these drugs. Cell lines from testicular teratoma cell lines may show exquisite sensitivity to temozolomide and this level of sensitivity is seen only occasionally in short-term cultures derived from malignant glioma.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Resveratrol and quercetin are polyphenols which have been detected in significant amounts in green vegetables, citrus fruits and red grape wines. Beneficial effects attributed to these compounds Include anti-Inflammatory, antiviral and antitumor properties. The effect of resveratrol and quercetin on growth of human oral cancer cells is unknown. Resveratrol and quercetin, in concentrations of 1 to 100 μM, were incubated in triplicates with human oral squamous carcinoma cells SCC-25 in DMEM-HAM's F-12 supplemented with fetal calf serum and antibiotics in an atmosphere of 5% CO2in air at 37°C for 72 h. Cell growth was determined by counting the number of viable cells with a hemocytometer. Cell proliferation was measured by means of incorporation of [3H]thymidine in nuclear DNA. Resveratrol at 10 and 100 μM induced significant dose-dependent inhibition in cell growth as well as in DNA synthesis. Quercetin exhibited a biphasic effect, stimulation at 1 and 10 μM, and minimal inhibition at 100 μM in cell growth and DNA synthesis. Combining 50 μM of resveratrol with 10, 25 and 50 μM of quercetin resulted in a gradual and significant increase in the inhibitory effect of quercetin on cell growth and DNA synthesis. We conclude that resveratrol or a combination of resveratrol and quercetin, in concentrations equivalent to that present in red wines, are effective inhibitors of oral squamous carcinoma cell (SCC-25) growth and proliferation, and warrant further investigation as cancer chemopreventive agents.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The clinical development of combinations of clsplatin or carboplatin with DNA topoisomerase I (Topo I) inhibitors is based on their overlapping spectrum of antitumor activity and theirIn vitrosynergy, but is limited by significant hematotoxicity. We studied the cellular Interactions between oxaliplatin and topotecan in the IGROV-1 human ovarian cancer cell line prior to evaluating the combination In the clinic. Growth inhibition was studied after a 96 h exposure to oxaliplatin and topotecan. The analysis of the cytotoxicity by the Isobolograms method revealed supra-addltivity with maximal cytotoxicity obtained by giving oxaliplatin prior to topotecan. In the presence of topotecan, the formation of oxallplatln-induced DNA Interstrand crosslinks was not modified in cells, but their reversion was slower, as measured by alkaline elution. Successive topotecan exposures did not affect the level of Topo l-mediated DNA single-strand breaks (SSBs). Pre-exposure to oxaliplatin transiently increased Topo l-mediated SSBs, suggesting that DNA platination might stimulate Topo I DNA cleavage activity. Hence, the cellular pharmacology of oxaliplatin combined with topotecan appeared highly dependent on the schedule. Therefore, this study suggests that the combination of topotecan with oxaliplatin might exhibit sequence-dependent pharmacodynamic interactions in the clinic.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Na+,K+-ATPase (EC 3.6.1.37) is assumed to be involved in the transport of cisplatin [cis-diamminedichloroplatinum(II)] into cells and to act as a modulator of 5-fluorouracil (5-FU) in combination therapy of cisplatin and 5-FU. Whereas inhibition of Na+,K+-ATPase activity by cisplatin is expected to have effects on both anti-cancer therapy and nephrotoxicity, the inhibition mechanism remains to be elucidated. We studied the inhibition of Na+,K+-ATPase activity by cisplatin using an enzyme partially purified from Ca9–22 cells derived from a human squamous cell carcinoma of the gingiva. Cisplatin inhibited the Na+,K+-dependent ATP hydrolysis activity, and this inhibition depended on both the concentration of cisplatin and the preincubation time with cisplatin. The time-dependent inhibition was thought to be caused by a slow change of cisplatin from the inactive to the active form. We further tested the effect of cisplatin on the partial reactions of the enzyme, Na+-dependent ATP hydrolysis and K+-dependentp-nitrophenylphosphate hydrolysis activities to determine which step in the reaction sequence of Na+,K+-ATPase was inhibited. Cisplatin inhibited both activities depending on its concentration and the preincubation time, whereas the Na+-dependent ATP hydrolysis activity was inhibited even at lower concentrations. Formation of a phosphointermediate of Na+,K+-ATPase was also inhibited by cisplatin depending on the concentration and preincubation time. Cisplatin (500 μM) and 8-fold higher concentration of 2-mercaptoethanol (2-ME; 4 mM) prevented inactivation of the enzyme by cisplatin, and the Na+,K+-ATPase activity inhibited by pretreatment with cisplatin was also recovered almost completely by 2-ME. These results suggest that the active form of cisplatin inhibits the Na+,K+-ATPase activity by inhibiting the formation of a phosphointermediate of the enzyme and that the inhibition by cisplatin is arrested by an addition of thiol group.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

We have designed and used anin vitrobone marrow cell culturlng system for investigating pharmacodynamic interactions between platinum anti-cancer drugs and taxanes. With this system, In which the bone marrow progenitor cell CFU-GM is proliferating and differentiating into granulocytes and monocytes, we could show a strong antagonistic cytotoxicKy of the combination carboplatin and Taxotere, in three different schedules, and of the combination cisplatin and Taxol, In two out of the three schedules tested. Modulation of intracellular platinum drug accumulation in granulocytes and monocytes does not seem to be a plausible explanation for the observed antagonism.In vitroco-incubation of granulocytes/monocytes with the combination carboplatin and Taxotere did not reveal an effect of Taxotere on intracellular platinum accumulation. Although Taxol reduced Intracellular cisplatin levels by 12%, this effect was not significantly different from the co-incubation of cisplatin with Cremophor EL, the solvent for paclKaxel in Taxol. The toxicity data obtained in this study seem to be in accordance with recent clinical trials where combination therapies with platinum drugs and taxanes resulted in marked reductions in myelosuppresslon in patients. Therefore, these types of assays could be useful as to the assessment of bone marrow toxicities of clinically Important drug combinations.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID