Epigenetic aberrations have been reported in hepatocellular carcinoma (HCC). In this study of patients with unresectable HCC and chronic liver disease, epigenetic therapy with the histone deacetylase ...inhibitor belinostat was assessed. The objectives were to determine dose-limiting toxicity and maximum-tolerated dose (MTD), to assess pharmacokinetics in phase I, and to assess activity of and explore potential biomarkers for response in phase II.
Major eligibility criteria included histologically confirmed unresectable HCC, European Cooperative Oncology Group performance score ≤ 2, and adequate organ function. Phase I consisted of 18 patients; belinostat was given intravenously once per day on days 1 to 5 every 3 weeks; dose levels were 600 mg/m(2) per day (level 1), 900 mg/m(2) per day (level 2), 1,200 mg/m(2) per day (level 3), and 1,400 mg/m(2) per day (level 4). Phase II consisted of 42 patients. The primary end point was progression-free survival (PFS), and the main secondary end points were response according to Response Evaluation Criteria in Solid Tumors (RECIST) and overall survival (OS). Exploratory analysis was conducted on pretreatment tumor tissues to determine whether HR23B expression is a potential biomarker for response.
Belinostat pharmacokinetics were linear from 600 to 1,400 mg/m(2) without significant accumulation. The MTD was not reached at the maximum dose administered. Dose level 4 was used in phase II. The median number of cycles was two (range, one to 12). The partial response (PR) and stable disease (SD) rates were 2.4% and 45.2%, respectively. The median PFS and OS were 2.64 and 6.60 months, respectively. Exploratory analysis revealed that disease stabilization rate (complete response plus PR plus SD) in tumors having high and low HR23B histoscores were 58% and 14%, respectively (P = .036).
Epigenetic therapy with belinostat demonstrates tumor stabilization and is generally well-tolerated. HR23B expression was associated with disease stabilization.
We analyzed hTERT splicing patterns with respect to telomerase activity in breast cancer. Using a cDNA microarray in 22 cell lines, we observed the difference in expression profiling based on the ...different levels of full-length variant expression with 71 selected genes. Using 33 known genes that act with the telomerase complex, we performed unsupervised clustering with all cell lines, and found a clustering tendency related to the full-length variant expression level. Using array-based CGH, highly altered genomic copy number changes were found more often in MCF-7 (159 genes) than in MDA-MB-231 (109 genes) and MDA-MB-435 (49 genes), suggesting more genomic changes in MCF-7 cells. On comparing MCF-7 with MDA-MB231 and MDA-MB-435 cell lines, we identified 8 genes with different copy numbers, including dystroglycan, which is located in the p12-21.2 area of chromosome 3. In conclusion, alterations in the level of the full-length variant of hTERT showed different gene expression profiles and genomic copy number changes in breast cancer, which require further study into their cause-and-effect relationship.
The authors evaluated the efficacy of adjuvant chemotherapy with 5-fluorouracil (5-FU) plus doxorubicin in gastric carcinoma after D2-3 curative resection. They also evaluated the effect of ...dose-related factors (delivered total dose/m(2), actual dose intensity ADI, relative dose intensity RDI) of this regimen on patient survival.
A total of 301 patients with Stage II to IV (en bloc resected T4b; 1984 American Joint Committee on Cancer staging) were accrued between 1984 and 1996. Chemotherapy was started within 4 weeks of surgery according to the following schedule: intravenous bolus injection of doxorubicin 40 mg/m2 every 3 weeks for 12 cycles and 5-FU 400 mg/m2 weekly for 60 weeks. The toxicity and survival were evaluated.
The median follow-up duration was 58 months. Sixty-four percent of the total patients and 71.7% of the patients who did not experience recurrence during the chemotherapy finished the protocol completely with acceptable toxicities. The 5- and 10-year disease free survival rates of total 301 patients were 58.4% and 46.5%, and the overall survival rates were 62.1% and 50.5%, respectively. Treatment completion group showed survival benefit over the early termination group in 5-year survival (75.2% vs. 52.9%; P = 0.0005). The median ADI of 5-FU and doxorubicin were 349 and 11 mg/m2/week, and the median RDIs of 5-FU and doxorubicin were 0.87 and 0.83, respectively. Multivariate analysis demonstrated that completion of chemotherapy is an independent prognostic factor of both disease free and overall survival. However, ADI and RDI did now show any effect on survival.
Adjuvant chemotherapy with 5-FU plus doxorubicin for 60 weeks after D2-3 dissection induced promising survival duration with acceptable toxicities. Full administration of the planned dosage of the combined drugs is recommendable as opposed to early termination of the chemotherapy in gastric carcinoma.
We investigated the dose-related effect of the 5-fluorouracil (5-FU)/leucovorin regimen on survival in 139 colon cancer patients with Dukes’ B2 and C2 stage disease. Chemotherapy consisted of 400 ...mg/m
2 of 5-FU and 20 mg/m
2 of leucovorin injected daily for 5 days in every 4 weeks for a maximum of 12 cycles. The total dose of 5-FU administered per body surface area had a significant effect on the 5-year disease-free survival and 5-year overall survival in stage B2 and C2 colon cancer patients (
P=0.0018,
P=0.0011). Analysis with reference to the median DSDI demonstrated that there was a significant difference in 5-year survival in Dukes’ C2 (
P=0.0016), but survival was not affected by the dose intensity. Multivariate analysis demonstrated that only the total dose of 5-FU administered per surface area affected the 5-year disease-free survival and 5-year overall survival (
P=0.0016,
P=0.0007, respectively). It can be concluded that the total dose of 5-FU administered is important in planned dosage schedule of adjuvant chemotherapy in colon cancer.
We evaluated the efficacy and tolerability of a combination chemotherapy including infusional fluorouracil (5-FU), etoposide, and cisplatin (FEP) in 89 patients with advanced/relapsed gastric cancer. ...Primary endpoints were progression-free and overall survival. Secondary endpoints were response rates, response duration, and toxicity. The treatment schedule was as follows: 5-FU 1,000 mg/m2 and etoposide 100 mg/m2 were administered on 3 consecutive days and cisplatin at 80 mg/m2 was administered on day 2, and repeated every 3 weeks. The median times to progression and overall survival were 4 and 8 months, respectively. One-year progression-free and overall survival rates were 10% and 33%, respectively. The overall response rate for 25 eligible patients with measurable disease was 20% (5/25, complete response 2, partial response 3) with median response duration of 7 months. Median actual dose intensities of 5-FU, etoposide, and cisplatin were 700 mg/m2/wk, 70 mg/m2/wk, and 21 mg/m2/wk, respectively. Median relative dose intensities of 5-FU, etoposide, and cisplatin were 0.70, 0.70, and 0.63, respectively. In conclusion, the FEP regimen was found to produce therapeutic results similar to those of other combination chemotherapeutic studies and to have an acceptable toxicity. This regimen could be used as one of the options for advanced gastric cancer chemotherapy in patients unsuitable for doxorubicin-based regimens.
In the postgenome era, a prediction of response to treatment could lead to better dose selection for patients in radiotherapy. To identify a radiosensitive gene signature and elucidate related ...signaling pathways, four different microarray experiments were reanalyzed before radiotherapy.
Radiosensitivity profiling data using clonogenic assay and gene expression profiling data from four published microarray platforms applied to NCI-60 cancer cell panel were used. The survival fraction at 2 Gy (SF2, range from 0 to 1) was calculated as a measure of radiosensitivity and a linear regression model was applied to identify genes or a gene set with a correlation between expression and radiosensitivity (SF2). Radiosensitivity signature genes were identified using significant analysis of microarrays (SAM) and gene set analysis was performed using a global test using linear regression model. Using the radiation-related signaling pathway and identified genes, a genetic network was generated. According to SAM, 31 genes were identified as common to all the microarray platforms and therefore a common radiosensitivity signature. In gene set analysis, functions in the cell cycle, DNA replication, and cell junction, including adherence and gap junctions were related to radiosensitivity. The integrin, VEGF, MAPK, p53, JAK-STAT and Wnt signaling pathways were overrepresented in radiosensitivity. Significant genes including ACTN1, CCND1, HCLS1, ITGB5, PFN2, PTPRC, RAB13, and WAS, which are adhesion-related molecules that were identified by both SAM and gene set analysis, and showed interaction in the genetic network with the integrin signaling pathway.
Integration of four different microarray experiments and gene selection using gene set analysis discovered possible target genes and pathways relevant to radiosensitivity. Our results suggested that the identified genes are candidates for radiosensitivity biomarkers and that integrin signaling via adhesion molecules could be a target for radiosensitization.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Plekha7 (Pleckstrin homology PH domain containing, family A member 7) regulates the assembly of proteins of the cytoplasmic apical zonula adherens junction (AJ), thus ensuring cell-cell adhesion and ...tight-junction barrier integrity. Little is known of Plekha7 function in cancer. In colorectal cancer (CRC) Plekha7 expression is elevated compared to adjacent normal tissue levels, increasing with clinical stage. Plekha7 was present at plasma membrane AJ with wild-type KRas (wt-KRas) but was dispersed in cells expressing mutant KRas (mut-KRas). Fluorescence lifetime imaging microscopy (FLIM) indicated a direct Plekha7 interaction with wt-KRas but scantily with mut-KRas. Inhibiting Plekha7 specifically decreased mut-KRas cell signaling, proliferation, attachment, migration, and retarded mut-KRAS CRC tumor growth. Binding of diC8-phosphoinositides (PI) to the PH domain of Plekha7 was relatively low affinity. This may be because a D175 amino acid residue plays a “sentry” role preventing PI(3,4)P2 and PI(3,4,5)P3 binding. Molecular or pharmacological inhibition of the Plekha7 PH domain prevented the growth of mut-KRas but not wt-KRas cells. Taken together the studies suggest that Plekha7, in addition to maintaining AJ structure plays a role in mut-KRas signaling and phenotype through interaction of its PH domain with membrane mut-KRas, but not wt-KRas, to increase the efficiency of mut-KRas downstream signaling.
A major impediment to cancer treatment is the development of resistance by the tumor. P‐glycoprotein (P‐gp) and multidrug resistance protein 1 (MRP1) are involved in multidrug resistance. In addition ...to the extrusion of chemotherapeutic agents through these transporters, it has been reported that there are differences in the intracellular distribution of chemotherapeutic agents between drug resistant cells and sensitive cells. Cepharanthine is a plant alkaloid that effectively reverses resistance to anticancer agents. It has been previously shown that cepharanthine is an effective agent for the reversal of resistance in P‐gp‐overexpressing cells. Cepharanthine has also been reported to have numerous pharmacological effects besides the inhibition of P‐gp. It has also been found that cepharanthine enhanced sensitivity to doxorubicin (ADM) and vincristine (VCR), and enhanced apoptosis induced by ADM and VCR of P‐gp negative K562 cells. Cepharanthine changed the distribution of ADM from cytoplasmic vesicles to nucleoplasm in K562 cells by inhibiting the acidification of cytoplasmic organelles. Cepharanthine in combination with ADM should be useful for treating patients with tumors. (Cancer Sci 2005; 96: 372–376)
PDF
