摘要:

Chemotherapy of cancer based on cytotoxic agents has proved successful in the treatment of many cancers. The number of agents available to the oncologist has grown steadily and drug combinations are in widespread use. The perceived success of these combinations makes the introduction of new agents difficult. For any new agent, multiple phase II and III trials are likely to be needed. Since phase II/III trials usually only address single issues, the cost of introducing a new agent is substantial. Multiple studies are required with different tumor types to define the activity profile of a new drug, followed by adjusted combinations to define the role of the new drug in conjunction with older ones. Recent advances in the understanding of cancer at a molecular level are already leading to new agent design. The next problem is how to introduce and use these agents. One possible approach is to trial the drugs with tumor cellsex vivo, using a chemosensitivity assay such as the ATP-based chemosensitivity assay which is designed to mimic the situation within the tumor accurately enough to examine issues of dose response, sequence and timing in many different tumors. The avoidance of cell lines ensures relevance and the sensitivity of some of these methods allows large numbers of mechanistically logical permutations to be tested with material from small numbers of patients. The results may be used to choose the most effective combinations for clinical testing in a limited number of subsequent phase II/III trials, saving money and time, while permitting new agents to be introduced faster.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Advanced melanoma has a poor prognosis and chemotherapy provides little benefit for most patients. This may be related to heterogeneity of chemosensitivity as well as frequent constitutive resistance to individual cytotoxic drugs. We have therefore examined the heterogeneity of chemosensitivity in metastatic cutaneous melanoma specimens using anex vivoATP-based chemosensitivity assay (ATP-TCA). Melanoma deposits (n=55) in skin or lymph node were tested using the ATP-TCA, performed in three separate laboratories. Analysis of the data collected (based on an arbitrary sensitivity index <300) shows considerable heterogeneity of chemosensitivity. The most active single cytotoxic agents in the assay were identified as cisplatin, treosulfan, paclitaxel, vinblastine, gemcitabine and mitoxantrone. There was also a limited direct inhibition of melanoma cell growth by interferon-α2b, although this agent is known to have a number of indirect biological antitumor effects. Exposure of tumor cells to combinations of drugs at the concentrations tested as single agents showed the most active combinations to be treosulfan+gemcitabine, cisplatin+paclitaxel and vinblastine+paclitaxel. There was considerable heterogeneity of chemo sensitivity: some tumors responded well to one agent or combination, while others showed no response to this and instead responded to one of the alternatives tested. Occasional highly resistant tumors showed no response to any of the single agents or combinations tested. The degree of heterogeneity observed suggests that the ATP-TCA could be used to select patients who might benefit from specific chemotherapeutic agents alone or in combination. This provides the rationale for future randomized controlled trials of ATP-TCA-directed chemotherapy versus physician's choice to determine whether assay-directed chemotherapy can improve patient response and survival.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Both gemcitabine (2‘,2’-difluorodeoxycytidine, dFdC) and cisplatin (cis-diammine-dichloroplatinum) have significant anticancer activity against ovarian, head and neck, and non-small cell lung cancer (NSCLC). dFdC can be incorporated into DNA and RNA, and inhibit DNA repair, while cisplatin can form Pt-DNA adducts. We previously observed schedule-dependent synergism of the combination of dFdC and cisplatin in monolayer cell cultures. We now evaluated whether the combination would also enable selective cell kill in multilayered postconfluent cell cultures, since each compound showed variable activity in multilayered cells. The combination was tested in multilayered cultures from cell lines with a different histological origin: the human head and neck squamous cell carcinoma cell line UMSCC-22B (22B), the human NSCLC cell line H322, and ADDP, a cisplatin-resistant variant of the human ovarian cancer cell line A2780. Sensitivity of the multilayered cells was dependent on exposure duration and sequence of the drug combinations, which were added in a constant molar ratio (dFdCxisplatin 1:100), with a total exposure time of 96 h. The type of interaction was related to the degree of resistance of the cell lines to either dFdC or cisplatin. Thus, the very sensitive 22B cells only showed an additive effect when cells were preincubated for 24 h with dFdC prior to exposure to the combination. In contrast, in the resistant ADDP and H322 cells, synergism was the most common profile (three out of four schedules tested). This is of special relevance when we take into account that these drugs only show cytostatic effects when administered alone, whereas the combination produced cytotoxic cell killing. In conclusion, combining dFdC with cisplatin can be at least additive, but synergistic in multilayered postconfluent cells resistant to dFdC and cisplatin.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

This phase II study investigated the activity of continuously administered oral trofosfamide in chemotherapy-pretreated patients with metastatic soft-tissue sarcoma (STS). Trosfosfamide is an oxazaphosphorine with ifosfamide as the predominant metabolite. Eighteen patients with a median age of 60 years were treated with trofosfamide given as continuous oral treatment. Starting dose was 300 mg/day for 7 days and subsequently 150 mg/day. All patients had previously received at least one chemotherapy regimen including doxorubicin and ifosfamide. Three patients achieved partial responses (18%) and nine a disease stabilization (53%) for an overall response rate of 18% (95% Cl: 0.5–35%). Median progression-free interval was 4 months (0–17 months) and median overall survival was 10 months (4–39+) months. Toxicity was generally mild. Only one WHO grade III nausea, but no other non-hematologic WHO grade III/1V toxicity occurred. Leukopenia WHO grade III/IV was observed in four patients (22%). No thrombocytopenia <50 000/μl and no neutropenic infection was seen. Continuously administered oral trofosfamide is a well-tolerated palliative treatment in anthracycline/oxazaphosphorin-pre-treated patients with advanced STS achieving responses and/or disease stabilization in up to 70% of patients.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Murine L1210 leukemia cells possessing an increased resistance to cisplatin were found to be refractory to transforming growth factor (TGF)-β1-induced growth inhibition, while the parental L1210 cells were strongly inhibited by this cytokine. Growth inhibition was estimated on the basis of [3H]thymidine incorporation, cell counting and colony-forming assay. Cisplatin-resistant L1210 cells were also shown to be much more resistant than the parental cells to both cisplatin-and TGF-β1-induced apoptosis. These results suggest the existence of cross-resistance to cisplatin and TGF-β1 in the studied leukemia cells.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Granisetron has been shown to exert a beneficial therapeutic effect in the prophylaxis and treatment of acute nausea and vomiting due to chemotherapy. However, limited data regarding its efficacy in the prevention and treatment of delayed emesis are available. A total of 532 patients entered this multicenter double-blind study, aimed at comparing the efficacy and safety of intramuscular (i.m.) granisetron with that of i.m. granisetron plus dexamethasone. Complete response and total control were evaluated for 3 days following the first 24 h after cisplatin administration in two groups of patients: 262 treated with granisetron 3 mg i.m. daily (plus placebo), and 265 with granisetron at the same dose plus dexamethasone 8 and 4 mg twice daily. The rate of complete response was 58.0% in the granisetron group and 78.9% in the granisetron plus dexamethasone group over days 1–3 (p<0.01). Similarly, over the same period total control was 44.7% with granisetron alone and 65.3% with granisetron plus dexamethasone (p<0.01). Local and systemic tolerability of the i.m. therapy with granisetron were satisfactory. In conclusion, granisetron plus dexamethasone showed good protection against delayed emesis due to emetogenic chemotherapy.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The retinoic acid receptor β (RAR β), a putative tumor suppressor gene, has been reported to be poorly expressed in breast cancer. In this report using the methylation-specific PCR reaction we observed DNA methylation in the promoter region of RAR β in several primary breast tumors. DNA sequence analysis showed that the positions of 5-methyl-cytosine in the RARβ promoter region was almost identical to that reported previously by our laboratory for human DLD-1 colon carcinoma cells (Anti-Cancer Drugs1998; 9: 743). Several other cancer-related genes have been also reported to be silenced by DNA methylation, including the p16 tumor suppressor gene, E-cadherin, an invasion suppressor gene and the estrogen receptor gene in breast cancer cell lines. Since breast cancer cells have several potential target genes for the DNA methylation inhibitor, 5-aza-2‘-deoxycytidine (5-Aza-CdR), we investigated thein vitroantineoplastic activity of this analog on the human breast cancer cell line MDA-MB-231. We report that 5-Aza-CdR is a potent growth inhibitor and a potent cytotoxic agent against the breast carcinoma cells. These results suggest that 5-Aza-CdR may be an interesting agent to investigate in patients with breast cancer resistant to conventional chemotherapy.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Gallium chloride (GaCI3), an antitumor agent with antagonistic action on iron, magnesium and calcium, was tested for its ability to alter the polymerization of purified tubulin (2.2 mg/ ml) in a cell-free systemin vitro. GaCI3(250 μM) does not mimic the effect of 10 μM paclitaxel and, therefore, is not a microtubule (MT)-stabilizing agent that can promote tubulin polymerization in the absence of glycerol and block MT disassembly. In contrast, GaCI3mimics the effect of 1 μM vincristine (VCR) and inhibits glycerol-induced tubulin polymerization in a concentration-dependent manner (IC50: 125 μM), indicating that GaCI3is a MT de-stabilizing agent that prevents MT assembly. However, 150 μM GaCI3must be used to match or surpass the inhibitions of tubulin polymerization caused by 0.25 μM of known MT de-stabilizing agents, such as colchicine (CLC), nocodazole, podophyllotoxin, tubulozole-C and VCR. The inhibitory effect of 250 μM GaCI3persists in the presence of up to 9 mM MgCI2, suggesting that the exogenous Mg2+cations absolutely required for the binding of GTP to tubulin and MT assembly cannot overcome the antitubulin action of Ga3+ions of a higher valence. The binding of [3H]vinblastine (VBL) to tubulin (0.5 mg/ml) is inhibited by unlabeled VBL but enhanced by concentrations of GaCI3> 200 μM. However, increasing concentrations of GaCI3mimic the ability of cold CLC to reduce the amount of [3H]CLC bound to tubulin, suggesting that GaCI3may interact with the CLC binding site to inhibit tubulin polymerization. The binding of [3H]GTP to tubulin is decreased by unlabeled GTP but markedly enhanced by GaCI3, especially when concentrations of this metal salt of 32 μM or higher are added to the reaction mixture before rather than after the radiolabeled nucleotide. These data suggest that changes in protein conformation following GaCI3binding might increase the interactions of tubulin with nucleotides and Vinca alkaloids. After a 24 h delay, the viability of GaCI3-treated L1210 leukemic cells is reduced in a concentration-dependent manner at days 2 (IC50:175 μM), 3 (IC50: 35 μM)and 4 (IC50:16 μM). Since GaCI3(100–625 μM) increases the percentage of mitotic cells at 2–4 days, it might arrest tumor cell progression in M phase, but its antimitotic activity is much weaker than that of 0.25 μM VCR. Because the concentrations of GaCI3that inhibit tubulin polymerization also increase the mitotic index and decrease the viability of L1210 cellsin vitro, the antitubulin and antimitotic effects of GaCI3might contribute, at least in part, to its antitumor activity.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Tricyclic pyrones (TPs) may represent a novel synthetic class of microtubule (MT) de-stabilizing anticancer drugs previously shown by us to inhibit macromolecule synthesis, tubulin polymerization, and the proliferation of leukemic and mammary tumor cellsin vitro. A linear skeleton with a N-containing aromatic ring attached at C3 of the top A-ring, a central pyran B-ring and a six-membered bottom C-ring with no alkylation at C7 are required for the antitumor activities of the lead compounds, a 3-pyridyl benzopyran (code name H10) and its somewhat weaker 2-pyridyl regioisomer (code name H19). Increasing concentrations of H10 do not alter the binding of [3H]vinblastine and [3H]GTP to tubulin but mimic the ability of unlabeled colchicine (CLC) to reduce the amount of [3H]CLC bound to tubulin, suggesting that TPs may interact with the CLC binding site to inhibit tubulin polymerization. Exogenous Mg2+cations absolutely required for the binding of GTP to tubulin and MT assembly cannot overcome the antitubulin action of H10. H10 reduces the viability of L1210 cellsin vitro(IC50: 0.5 μM) but its antitumor activity may be related to its ability to inhibit tubulin polymerization and rapidly increase the mitotic index rather than to induce DNA cleavage and apoptosis. The anticancer potential of TPsin vivois demonstrated by the fact that i.p. injections of the water-soluble H10-HCI decrease the growth of solid tumors in mice inoculated s.c. with Lewis lung carcinoma. A critical finding is that the antimitotic H10 is a bifunctional anticancer drug, which also blocks the cellular transport of nucleosides (IC50: 6 μM) to inhibit DNA synthesis. Since few CLC site-binding antimitotic agents are active in solid tumor modelsin vivo, the ability of these new MT destabilizing TPs to totally block nucleoside transport might be valuable in polychemotherapy to arrest tumor cells at several phases of their cycle, potentiate the action of antimetabolites and sensitize multidrug-resistant tumor cells.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

The cytotoxic effects of Tomudex® (TX) were investigated on a panel of 15 human tumor cell lines expressing a spontaneous sensitivity to the tested agent. We determined the basal cellular amount of relevant cellular factors potentially related to the cytotoxic efficacy of or resistance to TX. We selected thymidylate synthase (TS) as the target for TX, basal reduced folates (RF), because RF may compete with TX for a common site on the TS molecule. We also tested folylpolyglutamate synthetase (FPGS) because this is the enzyme which transforms the drug into its active polyglutamated form. Results were as follows. There was a wide inter-cell line variability in IC50values for TX and there were marked differences between cell lines for all tested biochemical parameters. No link was observed between basal cellular TS activity and TX cytotoxic efficacy. There was an inverse relationship between reduced folate cellular content and TX IC50values; this relationship did not, however, reach statistical significance. The only significant relationship was found between basal cellular FPGS activity and TX IC50r= −0.56,p= 0.03. Tumor cells with a relatively high FPGS activity were more sensitive to TX cytotoxic effects and vice versa. Along with previous results which showed that acquired resistance to TX is accompanied by a decrease in FPGS activity, the present data are strongly indicative of a prominent role played by FPGS activity in the intrinsic sensitivity to TX. Means to up-regulate FPGS activity with pharmacological or tumor-specific genetic approaches are recommended so as to optimize TX antitumor activity.

ISSN:0959-4973    

出版商:OVID    

年代:1999

数据来源: OVID