摘要:

Programmed cell death (apoptosis) is a conserved, natural mechanism for the removal of redundant and unwanted cells during normal development. This article reviews the evldence that apoptosls may also control the response of tumor cells to treatment with cytostatic drugs. Whereas most clinlcally used anti-cancer drugs can activate late events of apoptosis (DNA degradation and morphological changes) there are differences in essential signalling pathways between pharmological cell death and the physlological induction of an active sulclde programme. However, deregulation of normally integrated cell cycle progresslon appears a central signalling event in most forms of apoptosis, linking cell cycle control, DNA repair and cell death. Whether apoptosis is the cause or the consequence of drug-induced cell death remains to be established.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

During a phase I clinical and pharmacologic trial, 26 patients with refractory solid tumors were treated with increasing doses of adozelesin by brief intravenous Infusion every 3 weeks. Overall, adozelesin was well tolerated. The dose-limlting toxicity was myelosuppression, mainly thrombocytopenia and leukopenia. Nonhematologic toxicity was generally mild, with fatigue (36%), local reaction at the infusion slte (24%), nausea or vomlting (20%) and hypersensitivity reaction (16%) being the most common adverse effects. There were no objective clinical responses. The maximally tolerated dose on this schedule was 188 μg/m2with the recommended phase II starting dose being 150 μg/m2on an every 3 week schedule. Adozelesin merits broad investigation at the phase II level.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Several mutant Chinese hamster ovary (CHO) cell lines have been adapted to the microtiter tetrazollum assay in order to obtain useful mechanistic information relevant to the cytotoxic activity of marine natural products. The sensitivity of a DNA double-strand break repair deficient CHO line, xrs-6, was compared with that of a DNA repair competent CHO line, BR1, to several known drugs. The deficiency of the xrs-6 cells makes them overly sensitive to compounds [e.g. topoisomerase II (topo II) inhibitors] that produce DNA double-strand breaks. Described here is the valldation of this unique cellular screen to detect such compounds. Those drugs thought to produce their effects by the inhibition of topo if, produced the largest differential cytotoxicity agalnst the mutant CHO pair. Other agents that are known to either produce single-strand breaks, cross-links or to inhibit the synthesis of DNA did not possess appreciably enhanced cytotoxicity to the xrs-6 line. The usefulness of the screen was shown by its ability to detect topo II inhibitory activity in several new marine natural products. This activity was confirmed by anin vitroenzyme inhibition assay. In contrast, the screen predicted a lack of topo II inhibitory activity in some other structurally related marine natural products and this lack of activity was confirmed by anin vitroenzyme inhibition assay.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Thein vitroeffects of paclitaxel (Tx) and docetaxel (Taxotere, Txt) are compared in this study using the adenosine triphosphate cell viability assay (ATP-CVA) in 14 cancer cell lines. Eleven cell lines were sensitive and three were partially sensitive to paclitaxel. Nine cell lines were sensitive, three were partially sensitive and two were resistant to docetaxel. Mean IC50s were 3.7–660 ng/ml paclitaxel and 5.4–540 ng/ml docetaxel. In five sensitive cancer cell lines docetaxel was more active than paclitaxel, and in six sensitive cell lines paclitaxel was more active than docetaxel on a concentration basis. Two cell lines were sensitive to paclitaxel and resistant to docetaxel. In one cell line the two compounds had similar activities. In the ATP-CVA, paclitaxel and docetaxel are very active and are partially non-cross-resistant.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

We studied the acute toxicity and pathological effects of peplomycin adsorbed on fine activated carbon particles (PEP-CH) injected subcutaneously in mice. The 50% lethal dose value was 41.2 mg/kg in terms of peplomycin, which was 1.52 times that of the peplomycin aqueous solution (PEP-AQ) of 27.1 mg/kg. Deaths occurred from 5 to 31 days after administration of PEP-CH and from 5 to 22 days after administration of PEP-AQ solution. These figures are remarkably different from another report in which the mice given PEP-AQ died within 10 days.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The modulating effect of ethyldeshydroxy-sparsomycin (EDSM), an inhibitor of ribosomal protein synthesis, on cytostatic agents was studied on cultured B16 melanoma cells using the microculture tetrazollum test (MTT). The data were analyzed for true synergism using the combination index and the median effect principle. The extent of cytotoxic drug interaction was influenced by the duration of drug exposure, the dose ratio, as well as the treatment schedule. When drug ratios were used, synergism was observed upon pre- and post-treatment in combination with cisplatin, cytosine arabinoside (Ara-C), methotrexate (MTX) and 5-fluorouracll (5-FU). The combination of a fixed dose of EDSM was synergistic with clsplatin, Ara-C, vincristine (VCR) and MTX, in the order MTX > Ara-C > VCR > cisplatin, while the combinations with doxorubicin, 5-FU and etoposide (VP-16) were shown to be antagonistic. These results suggest that only certain drugs and treatment schedules might be worthwhile for combination studies with EDSMIn vivoand indicate a role for EDSM as modifier of antitumor responses in cancer chemotherapy.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

The toxicity and binding of the three new carborane based compounds: 2 (1,2-dicarba-closo-dodecaborane (12)-1(-yl-methoxy)-2-(3-amino-propyl))-1,3-propanedlol, called DAC-1; 7-(3-amino-propyl)-7,8-dicarba-nido-undecarborate (-1) called ANC-1; and rac-1-(9–0-carboranyl)-nonyl-2-methyl-glycero-3-phosphocholine, called B-Et-11-OMe, were analyzed with cultured human glloma cells, U-343MGa, and mouse melanoma cells, B16, as biological models. The prevlously developed compound di-sodium undecahydro-mercapto-closo-dodecarborate (BSH), which is tested for therapy of mallgnant gllomas, was analyzed for comparison. In the toxicity tests the cells were exposed to the substances at cell culture medium concentrations in the range 0–50 ppm boron for 1 or 20 h and thereafter analyzed regarding growth. Growth-disturbing effects were seen for the two compounds DAC-1 and B-Et-11-OMe at the concentrations corresponding to 15 and 50 ppm boron, respectively. The compounds ANC-1 and BSH showed no growth-disturbing effects at the tested concentrations. In the binding tests, the cells were Incubated for 20 h at about the highest compound concentrations that did not cause growth disturbances. The boron content in the cells was then determined by inductively coupled plasma–atomic emlssion spectrometry (ICP–AES) and in some cases ICP–mass spectrometry (ICP–MS). The most extensive binding was seen for DAC-1 and B-Et-11-OMe, which accumulated boron to about 100 and 60 times, respectively, compared with the concentration in the culture medium. The compound ANC-1 also accumulated boron in the cells but the boron could be easily washed out indicating no or only a weak binding. BSH did not accumulate. Further analysis should be made regarding blological properties such as intracellular compartmentallzation, metabolic interference and tumor specificity of the compounds DAC-1 and B-Et-11-OMe.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

In this study, we tried to definein vitrointeractions of two antitumor agents that have different sites and different mechanisms of action. Vinblastine (VLB) in combination with human recombinant interferon-α A/D (rHulFN-α A/D) and in combination with murine recombinant interferon-γ (rMulFN-γ) was studied. The effect of the combination was determined with cell growth kinetics assay on B-16 melanoma and the interaction defined by means of Spector's formula. Both the combination of rHulFN-α A/D with VLB and the combination of rMulFN-γ with VLB synergistically inhibited cell growthin vitro.There was a positive biochemical modulation between the two drugs, but it is still unknown whether it occurred at the level of uptake into the cell, metabolism within the cell or egress from the cell.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Glutaminase is a hematotoxic anti-tumor agent, and copper–ATP complex (Cu–ATP) is both anti-neoplastic and hematostimulatory. Combination chemotherapy with these two agents has been performed in mice bearing Ehrlich ascites carcinoma, to elucldate whether this could result in augmented tumor inhibition with reduced hematotoxicity. Glutaminase–Cu–ATP combination (glutaminase 250 IU/kg per day Intraperitoneally for 10 days and Cu–ATP 2.5 mg/kg per day intraperitoneally for 10 days) was observed to be more effective in inhibiting tumor growth and in increasing the life span of the tumor hosts, compared with the individual efficacies of these two agents. Moreover, addition of Cu–ATP successfully prevented the hematotoxic effects of glutaminase in normal and in tumor-bearing animals. Thus glutaminase in combination with Cu–ATP holds promise for an effective cancer chemotherapeutic regimen.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Liposomalcis-bis-neodecanato-trans-R,R-1,2-diaminocyclohexaneplatinum (11) (L-NDDP) is a liposome-entrapped platinum complex that has shown partial lack of cross-resistance with cisplatin in human colon carclnoma LoVo cells. We studied the drug accumulation and DNA damage induced by L-NDDP and cisplatin in LoVo and LoVo/PDD cells. Our results indicate that the accumulation of L-NDDP in LoVo cells is several-fold higher than that of cisplatin; that the accumulation of L-NDDP is simillar in both cell lines, whereas that of cisplatin is reduced by 2− to 3-fold in LoVo/PDD cells; and that the transmembrane transport of cispiatin is highly dependent on temperature while that of L-NDDP is not. We also found that the cytotoxicity of both agents correlates with the extent of DNA–protein cross-link formation, and that DNA interstrand cross-linking does not appear to play a role in the cytotoxicity of L-NDDP, whereas it correlates with clsplatin cytotoxicity.

ISSN:0959-4973    

出版商:OVID    

年代:1994

数据来源: OVID