摘要:

Surgery is currently the first-line treatment option for primary colorectal cancer (CRC) and resectable metastatic disease. Cytotoxic chemotherapy is used for adjuvant treatment as well as for the treatment of advanced disease; the combination of 5-fluorouracil (5-FU) plus leucovorln Is currently the standard chemotherapeutic regimen used In most centers. In many countries patients with CRC do not receive chemotherapy because some clinicians perceive that the benefits of such treatment do not compensate for the potential negative effects on patient quality of life in terms of toxlcity and Inconvenient dosage schedules. However, recent evidence suggests that the use of cytotoxic chemotherapy can lead to an Improvement in quality of life and effective palliation In CRC. A number of new treatment options are becoming available for the treatment of this malignancy. These include new antlcancer agents such as thymidylate synthase inhibitors, monoclonal antibodies and topolsomerase I inhibitors, and new treatment methods including hepatic arterial or i.p. chemotherapy, cryosurgery and chemo-embolization. With the increased referral of patients to oncologists and the use of a multldlscipllnary team approach, these new agents and new methods of treatment can be fully evaluated for the treatment of CRC, and should ultimately improve the treatment and outcome of this common disease.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Chemotherapy for breast cancer is given on the basis of empirical information from clinical trials, an approach which fails to take into account the known heterogeneity of chemosensitivity between patients. Previous attempts to determine chemosensitivityex vivohave been disappointing, but in this study results from a newly developed tumor chemosensitivity assay (TCA) have been correlated prospectively with patient response. In this study, we have used heterogeneity data for standard regimens obtained from 116 breast TCAs to set sensitivity/resistance thresholds which were then used to interpret the results from those with known clinical responses. Assay evaluability was 97% in surgical biopsies. Clinical follow-up of stage III/ IV assessable disease was obtained from 27 breast tumors which were successfully tested for chemosensitivity, including 13 needle biopsies. The ATP-TCA assay predicted response correctly in 22 out of 29 (76%) tumors with clinically evaluable disease, suggesting that it is capable of predicting outcome in individual patients. Assays were performed in seven patients before and after chemotherapy using residual or recurrent tumor tissue. Four cases with initial sensitivity showed a decrease in sensitivity within 6 months of starting chemotherapy, while two others without clinical resistance were still sensitive by TCA. All nine courses of therapy given on the basis of TCA sensitivity resulted in partial or complete responses. Controlled trials of TCA-directed treatment against standardized empirical therapy should be conducted before this technology is widely adopted to assess its impact on rates of response, survival and the cost of treatment.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Anthracenyl-amino acid and dipeptlde conjugates represent new classes of topoisomerase (topo) inhibitors. To investigate the structural basis for their different selectivity against topo I and II and varying potency, the binding of six compounds to d(CGTACG) was studied by molecular modeling. Modeling data were in good agreement with physical data showing that five compounds intercalated DNA with the anthraquinone chromophore orientated in parallel to the long dimension of the d(CpG) base pairs and the amino acid placed in the minor groove. Differences in binding modes emerged which correlated to different biological properties. The amino acid chain of the topo I inhibitor (NU/ICRF 600, gly-phe) extended significantly out from the helical axis horizontal. The amino acid side chains of two topo II Inhibitors (NU/ICRF 510, arginine and NU7 ICRF 512, methionine) were Inserted into the minor groove, whereas the C-terminal groups (hydrazlde) of two potent topo II inhibitors (NU/ICRF 500 and 506, serine) were placed into the minor groove while the amino acid side chains pointed away from the minor groove. These data provide structural information which may prove valuable in rational design of second generation analogs.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Water-soluble paclitaxel may cause less side effects and be less costly to administer In comparison to a taxol formulation using a cremophor EL/alcohol vehicle. In this study, polyethylene glycol (PEG; MW 5000) was conjugated to the 2' position of paclitaxel through a spacer succlnyl group. PEG paclitaxel as a non-Ionic paclitaxel prodrug was highly water soluble (>20 mg equlv. paclitaxel/ml). The release of paclitaxel from phosphate-buffered solution was pH dependent. The half-life of PEG paclitaxel was 7.6, 54 and 311 min at pH 9.0, 7.4 and 6.0, respectively. PEG paclitaxel inhibited the growth of B16 melanoma cells to an extent similar to that of paclitaxel. In MCA-4 mammary tumor-bearing mice, a single dose of PEG-paclitaxel (40 mg equiv. paclitaxel/kg body weight) significantly delayed tumor growth. The average number of days for the tumor to reach 12 from 8 mm in diameter increased from 6.5 days for control animals to 8.5 days for PEG paclitaxeltreated animals and 9.4 days for paclitaxel-treated animals. These studies demonstrated that PEG may be used as an effective solubillzing carrier for paclitaxel.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The therapeutic performance, effect on quality of life and cost effectiveness of an orally administered medication in a home care setting were examined prospectively in a group of 61 patients presenting with advanced colorectal carcinoma. A regimen of daily ftorafur capsules (370 mg/m2) and leucovorin tablets (20 mg/m2) was offered to 35 symptomatic patients with poor performance status; the standard in-hospital i.v. protocol of 5-fluouracil and leucovorin was given to the remaining 26 patients. Follow-up and survival analysis indicated that there was no compromise in survival associated with home care and oral chemotherapy. There were statistically significant advantages in terms of reduced toxlcity and Improved Karnofsky performance status in this group. Home care was approximately 70% less expensive. A home treatment program based on oral ftorafur may be the most desirable option for all patients with advanced colorectal carcinoma.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Paclitaxel alone Is active against the CD8F1 murine spontaneous mammary cancer, and when administered following an ATP-depleting combination ofN-(phosphonacetyl)- L-aspartate (PALA) + 6-methylmercaptopurine riboside (MMPR) + 6-aminonicotinamide (6-AN) (PMA) produced significantly enhanced partial tumor regressions over that produced by either paclitaxel alone at the maximal tolerated dose (MTD), or by the PMA drug combination alone, against advanced, first passage spontaneous murine breast tumors. The anticancer activity of paclitaxel is due to enhancement and stabilization of microtubule polymerization. Pertinently, microtubule disassembly (an ATP-dependent process) is known to sharply decrease in the presence of ATP depletion. Thus, the dramatic therapeutic enhancement observed with paclitaxel in combination with PMA is in agreement with biochemical expectations, since PMA has been shown to deplete ATP in CD8F1 tumor cells. The augmented therapeutic results were obtained with approximately one-third the MTD of paclitaxel as a single agent and suggest the potential clinical benefit of more effective treatment with lesser amounts of drug.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The association of taxoid derivatives (paclitaxel and docetaxel) with irradiation was evaluated in ovarian carcinoma cell lines (A2780 and CAVEOC-2) using the multicellular tumor spheroids (MTS) tridimensional model and compared to the conventional bidimensional model. The radiosensitlvlty parameters were the surviving fraction at 2 Gy, and a calculated using the linear-quadratic model for monolayer culture, the residual/control volume ratios at 2Gy (RSV2) and doses inducing 50% decrease in MTS number (SCD50) calculated for spheroids. In A2780 monolayer culture, the combination was synergistic for paclitaxel and additive for docetaxel. In spheroids, both compounds induced a decrease in RSV2and SCD50in the two cell lines, and their combination with radiation was additive. Therefore, the radiosensitizing effect of taxoid derivatives was not constant in ovarian cell lines. The different results achieved in monolayer culture and in spheroids may suggest higher drug incorporation and fixation through the multiple cell layers of the spheroids than in monolayers.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The antiprogestatln drug mifepristone has previously been shown to potentiate anti-cancer drug activity in rodent multidrug-resistant cell lines through inhibition of P-glycoprotein (P-gp) function. In order to characterize P-gp mifepristone interactions in human tumoral cells, we have studied the effect of the antiprogestatin agent on P-gp activity in human CD34+leukemic cells known to display high levels of P-gp-related drug efflux. P-gp-mediated transport of the fluorescent dye rhodamine 123 occurring in the CD34+KG1a myeloid leukemia cell line was found to be strongly inhibited by mifepristone in a dose-dependent manner. Similarly to verapamil, a well-known chemosensitizer agent, the antiprogestatin drug increased doxorubicin cytotoxicity in KG1a cells. Mifepristone, when used at a 10 µ M concentration thought to be achievableIn vivowithout major toxicity, was also able to markedly decrease cellular rhodamine 123 efflux occurring in CD34+blast cells isolated from six patients suffering from myeloid acute leukemlas. These results thus indicate that mifepristone can strongly inhibit P-gp activity in human cells, including tumoral cells freshly isolated from patients, therefore suggesting that the clinical use of this compound may contribute to down-modulate P-gp-mediated drug resistance.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The effects of nine reversers of P-glycoprotein on the uptake of daunomycin into MDflf-transfected P388 cells were quantitatively determined in undiluted human or mouse plasma and compared with their effects when measurements are made in a conventional cell culture medium (RPMI 1640) containing only 10% serum. Plasma diminished or greatly diminished the effectiveness of the reversers, reductions of up to 20-fold being found for reversers (cyclosporin A, prochlorperazine and amiodarone) that have been used in clinical trials, although qulnldine was almost as effective in plasma as in cell culture medium containing 10% fetal calf serum. Human or bovine serum albumin could mimic the effect of whole plasma. When measurements of the effectiveness of the reverser cyclosporin A were made in an ex vivo assay, using these P388 cells, complete accord was found between suchex vivodeterminations and cyclosporin A's effectivenessIn vivo, as monitored by its ability to increase the accumulation of vinblastine in mouse kidney tissue. Theex vivoassay was shown to be suitable to monitor the effectivlty of reversers present in plasma taken from patients receiving quinidine and cyclosporin A in routine clinical treatment.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

After treatment of AH66DR cells with the multidrug resistance (MDR) phenotype with bovine serum albumin (BSA)- conjugated [14C]doxorubicin (DXR), accumulation of the drug in the secondary lysosomal fraction increased as a function of time up to 24 h without any significant increase of the drug in other organellae. By contrast, AH66P cells showed a marked increase in accumulation of the drug in the mitochondrial fraction, and a moderate increase in the lysosomal and nuclear fractions. The intracellular degradation of the internalized conjugate was assessed by HPLC gel filtration as molecular change of the drug. The initial molecular mass (Mr) of BSA-con|ugated [14C]DXR was estimated to be 70 kDa; however, the secondary lysosomal fraction contained mainly three peaks of [14C]compounds ranging from 3 to 70 kDa. The [14C]compound extracted from the nuclear and mitochondrial fractions showed only one peak, which was estimated to be smaller than 2 kDa. By contrast, the cytosolic fraction contained mainly two peaks of [14C]compounds, which were smaller than 2 kDa and larger than 500 kDa. These results indicated that the intracellular distribution of the administered drug, based probably on the drug-traffic mechanism in the cells, was quite different between the two cell lines, but some of the biochemical characteristics of the degraded compounds from each subcellular fraction were similar because the degradation processes in each fraction might be almost identical. The possibility of lysosomal degradation of the protein-conjugated DXR leading to expression of cytotoxicity was also confirmed by the fact that only lysosomal digestable poly-L-lysine-conjugated DXR exhibited dosedependent cytotoxicity against both cell lines in marked contrast to the cells treated with poly-D-lysine-conjugated DXR. It was concluded that lysosomal breakdown of protein-conjugated DXR, which had been taken up by endocytosis, and the liberation of the degraded active adducts of the conjugate without efflux by the MDR pump mechanism must be an essential stage in the development of the cytotoxicity against tumor cells with or without the MDR phenotype.

ISSN:0959-4973    

出版商:OVID    

年代:1996

数据来源: OVID