|
11. |
NB1011 induces Ser15 phosphorylation of p53 and activates the G2/M checkpoint |
|
Anti-Cancer Drugs,
Volume 14,
Issue 6,
2003,
Page 449-455
Ryan Dellinger,
Patricia Karjian,
Saskia Neuteboom,
Preview
|
PDF (191KB)
|
|
摘要:
NB1011, a phosphoramidate derivative of (E)-5-(2-bromovinyl)-2′-deoxyuridine, is a novel anti-cancer agent that selectively targets tumor cells expressing high levels of thymidylate synthase (TS), an enzyme required for DNA biosynthesis. NB1011 treatment of high-TS-expressing breast carcinoma cells (MCF7TDX) results in the induction of p53 and p21 protein levels, whereas no p53 or p21 induction is observed in the low-TS-expressing MCF7 tumor cells. Furthermore, MCF7TDX cells accumulate in the G2/M phase of the cell cycle in response to NB1011. In this study, the effect of NB1011 on the phosphorylation status of p53 was analyzed. We demonstrate that NB1011 treatment of various tumor cell lines expressing high TS results in the phosphorylation of p53 on Ser15, whereas this p53 phosphorylation is not observed in low-TS-expressing tumor cells. Also, we examined the role of several key cell cycle regulators in the growth inhibition observed in response to NB1011. Our results show that the mRNA and protein levels of the G2/M regulators cdc2, cyclin B1 and cdc25C are down-regulated in MCF7TDX cells, while unaffected in MCF7 cells. The mRNA and protein levels of 14-3-3σ, also a direct transcriptional target of p53, are up-regulated in MCF7TDX cells following NB1011 treatment, while unchanged in MCF7 cells. Taken together, our data indicate that the growth inhibition caused by NB1011 in MCF7TDX cells is mediated through phosphorylation of p53 and activation of the G2/M checkpoint.
ISSN:0959-4973
出版商:OVID
年代:2003
数据来源: OVID
|
12. |
Analysis of the antitumoral mechanisms of lipopolysaccharide against glioblastoma multiforme |
|
Anti-Cancer Drugs,
Volume 14,
Issue 6,
2003,
Page 457-466
Eun Won,
Michael Zahner,
Elizabeth Grant,
Pankaj Gore,
Michael Chicoine,
Preview
|
PDF (435KB)
|
|
摘要:
Our objective was to analyze the lipopolysaccharide (LPS) antitumoral effect upon glioblastoma, including whether the lipid A subunit alone can elicit glioblastoma regression, whether dexamethasone suppresses this response to LPS, whether B and T lymphocytes factor in this response, and whether this antitumoral effect of LPS provides resistance against subsequent challenge with glioblastoma. Mice (BALB/c, nude or SCID) implanted with s.c. DBT glioblastomas were treated with LPS (with or without dexamethasone) or with lipid A. A subset of BALB/c mice in which s.c. DBT glioblastomas had previously been eradicated using LPS were re-implanted with s.c. or intracranial (i.c.) DBT cells. For mice with s.c. tumors, mean tumor masses (MTM) were compared between groups. Survival was compared for mice with i.c. tumors. Lipid A caused near complete tumor regression of DBT glioblastomas in BALB/c mice (p<0.0001). Dexamethasone did not alter the antitumoral effect of LPS (p=0.48). LPS reduced the MTM of s.c. glioblastomas in T lymphocyte-deficient nude mice, but not as effectively as in immunocompetent mice. The antitumoral response to LPS for T and B lymphocyte-deficient SCID mice bearing DBT glioblastomas was similar to that for nude mice. Eradication of s.c. DBT glioblastoma in BALB/c provided partial resistance to subsequent challenge with s.c. or i.c. glioblastoma. We conclude that the LPS-mediated antitumoral response against glioblastoma is dependent upon the lipid A subunit of LPS, partially dependent upon T lymphocytes, independent of B lymphocytes, unaffected by dexamethasone and provides partial protection against subsequent challenges with glioblastoma.
ISSN:0959-4973
出版商:OVID
年代:2003
数据来源: OVID
|
13. |
Ex vivoeffects of the dual topoisomerase inhibitor tafluposide (F 11782) on cells isolated from fresh tumor samples taken from patients with cancer |
|
Anti-Cancer Drugs,
Volume 14,
Issue 6,
2003,
Page 467-473
Jean Sargent,
Alena Elgie,
Christine Williamson,
Bridget Hill,
Preview
|
PDF (174KB)
|
|
摘要:
Tafluposide (F 11782), a novel epipodophylloid with a unique mechanism of interaction with both topoisomerase I and II, has shown outstanding antitumor activityin vivoagainst a panel of experimental human tumor xenografts. The aim of this study was to evaluate its cytotoxicity against fresh tumor cells taken from patients. Cells derived from bone marrow, peripheral blood, malignant effusions or solid biopsies from 84 patients with either hematological or solid tumors were exposed continuously to 0.8–100 νM tafluposide for 48 h, 96 h or 7 days. Cell survival was measured using an MTT assay or the ATP assay and LC50values (drug concentration required for 50% cell kill) were calculated. Tafluposide showed significant cytotoxicity against cells derived from either hematological or solid tumors, with a marked inter-patient variation. There was no significant difference between the effect of tafluposide in samples from untreated or previously treated patients (p>0.05 for all cancer types). Whilst tafluposide appeared to show weak (p<0.05) cross-resistance with the topoisomerase II inhibitor etoposide in acute myeloid leukemia (AML), there did not appear to be any correlation with the effect of the topoisomerase I inhibitor topotecan (p>0.05) in either hematological or solid malignancies. True synergism was identified when combining tafluposide with cisplatin in ovarian cancer [combination index (CI)=0.14, 0.79] and with etoposide in AML (CI=0.49, 0.63 and 0.78). Our results suggest that tafluposide is a strong candidate for inclusion in clinical trials, particularly in hematological malignancies.
ISSN:0959-4973
出版商:OVID
年代:2003
数据来源: OVID
|
14. |
Effect of combination of TS-1 and low-dose cisplatin on sarcoma-180 mouse sarcoma |
|
Anti-Cancer Drugs,
Volume 14,
Issue 6,
2003,
Page 475-479
Yoshimasa Suzuki,
Yoshiro Ishibiki,
Ken Kawai,
Morio Sasaki,
Mitsuhiro Matsuda,
Tomoo Watanabe,
Tetsuhiko Shirasaka,
Toshiki Kamano,
Preview
|
PDF (97KB)
|
|
摘要:
TS-1 contains tegaful (FT), 5-chloro-2,4-dihydroxypyridine (CDHP; an inhibitor of 5-fluorouracil (5-FU) degradation) and potassium oxonate (Oxo; an inhibitor of 5-FU assimilation mainly in the digestive tract) in a molar ratio of 1:0.4:1. We evaluated the combination of TS-1 and low-dose cisplatin on mouse sarcoma. Male ddy strain mice at 6 weeks of age were s.c. transplanted with 5 × 106sarcoma-180 (S-1800) cells and divided into groups of seven animals each: Group A, no treatment; Group B, 5-FU alone by continuous i.p. infusion of 10 mg/kg with a minipump (Alzet); Group C, TS-1 10 mg/kg p.o. alone; Group D, cisplatin 0.2 mg/kg i.p. alone; Group E, B+D; Group F, C+D. Treatment was given for 5 days. Antitumor activity was evaluated on the basis of the tumor weight on day 8, and white blood cell count, red blood cell count, platelet count, BUN, GOT and GPT were determined to detect adverse effects. Tumor weights (g, mean±SD) were 0.54±0.15 in Group A, 0.52±0.17 in Group B, 0.34±0.05 in Group C, 0.46±0.12 in Group D, 0.34±0.07 in Group E and 0.16±0.03 in Group F. There were no noticeable adverse effects. The combined TS-1+cisplatin regimen showed considerably enhanced antitumor activities since sarcomas were significantly (p<0.05) decreased as compared with tissue. Mean AUC0–12(ng/ml·h) estimated in the groups receiving 5-FU+cisplatin or TS-1 alone was measured to calculate AUC0–12by the trapezoidal rule. 5-FU concentrations in blood and tumor from blood concentration data were 435 in Group B, 2651 in Group C, 343 in Group E and 1538 in Group F, while mean AUC0–12(ng/g·h) estimated from tumor tissue concentration data were 345 in Group B, 3548 in Group C, 324 in Group E and 2020 in Group F. Cisplatin acted as a modulator of 5-FU, suggesting clinical benefits of the combination of TS-1 and low-dose daily cisplatin.
ISSN:0959-4973
出版商:OVID
年代:2003
数据来源: OVID
|
15. |
Activity, pharmacokinetics and tissue distribution of TLC ELL-12 (liposomal antitumor ether lipid) in rats with transplantable, s.c. methylnitrosourea-induced tumors |
|
Anti-Cancer Drugs,
Volume 14,
Issue 6,
2003,
Page 481-486
Rupinder Bhamra,
Lois Bolcsak,
Imran Ahmad,
James Schupsky,
Patricia Roberts,
Rachel Stevens,
Christopher Cavanaugh,
Christine Swenson,
Preview
|
PDF (179KB)
|
|
摘要:
TLC ELL-12 is a liposomal formulation of the novel antineoplastic compound 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (L-ET-18-OCH3). The purpose of these studies was to evaluate the activity and tissue distribution of L-ET-18-OCH3when administered i.v. as TLC ELL-12 to rats bearing solid tumors. Growth-inhibitory activity of L-ET-18-OCH3and TLC ELL-12 against methylnitrosourea (MNU)-induced tumors grownin vitrowas evaluated. Female Buffalo rats were injected s.c. with transplantable MNU-induced tumor cells. Four days later, animals were treated i.v. with L-ET-18-OCH3administered as TLC ELL-12 once daily for 5 consecutive days. Another group of MNU-tumor bearing rats was given a single 12.5 mg/kg dose of TLC ELL-12 containing [14C]L-ET-18-OCH3by i.v. injection into a tail vein. The 50% growth inhibitory concentration for TLC ELL-12 against MNU tumor cellsin vitrowas 63 μM (about 30 μg/ml). Tumor growth was significantly inhibited in ELL-12-treated rats versus controls. After a single dose, whole blood L-ET-18-OCH3concentrations declined in a multiphasic fashion withCmaxand terminal half-life values of approximately 91.1 μg L-ET-18-OCH3/ml and 13.1 h, respectively. Tumor L-ET-18-OCH3levels increased through the first 16–24 h post-dosing to about 23 μg/g and remained elevated at the terminal time point with little evidence of metabolism. Concentration–time profiles for selected tissues indicate rapid distribution of L-ET-18-OCH3from the circulation into tissues with highest concentrations in spleen, liver, lungs, kidneys and gastrointestinal tract. L-ET-18-OCH3as TLC ELL-12 shows bothin vitroandin vivoactivity against the MNU tumor line. When i.v. administered, L-ET-18-OCH3from ELL-12 is well distributed and slowly eliminated by metabolism in tissues.
ISSN:0959-4973
出版商:OVID
年代:2003
数据来源: OVID
|
|