摘要:

Histone deacetylase (HDAC) inhibitors are emerging as an exciting new class of potential anticancer agents for the treatment of solid and hematological malignancies. In recent years, an increasing number of structurally diverse HDAC inhibitors have been identified that inhibit proliferation and induce differentiation and/or apoptosis of tumor cells in culture and in animal models. HDAC inhibition causes acetylated nuclear histones to accumulate in both tumor and normal tissues, providing a surrogate marker for the biological activity of HDAC inhibitorsin vivo. The effects of HDAC inhibitors on gene expression are highly selective, leading to transcriptional activation of certain genes such as the cyclin-dependent kinase inhibitor p21WAF1/CIP1but repression of others. HDAC inhibition not only results in acetylation of histones but also transcription factors such as p53, GATA-1 and estrogen receptor-&agr;. The functional significance of acetylation of non-histone proteins and the precise mechanisms whereby HDAC inhibitors induce tumor cell growth arrest, differentiation and/or apoptosis are currently the focus of intensive research. Several HDAC inhibitors have shown impressive antitumor activityin vivowith remarkably little toxicity in preclinical studies and are currently in phase I clinical trial. The focus of this review is the development and clinical application of HDAC inhibitors for the treatment of cancer.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

XR11576, a novel phenazine, was developed as an inhibitor of both topoisomerase I and II. This study characterized the ability of XR11576 to inhibit both enzymes, and determined itsin vitroandin vivoantitumor efficacy against a number of murine and human tumor models. XR11576 was a potent inhibitor of purified topoisomerase I and II&agr;, and exhibited similar potency for both enzymes. The compound stabilized enzyme–DNA cleavable complexes indicating that it acted as a topoisomerase poison. The DNA cleavage patterns obtained with XR11576 were different from those induced by camptothecin and etoposide, which are topoisomerase I and II poisons, respectively. XR11576 demonstrated potent cytotoxic activity against a variety of human and murine tumor cell lines (IC50=6–47 nM). Its activity profile was comparable to or better than that of many widely used anticancer drugs. Moreover, XR11576 was unaffected by multidrug resistance (MDR) mediated by overexpression of either P-glycoprotein or MDR-associated protein, or by down-regulation of topoisomerase II. The latter property supports the dual inhibitory mechanism of action of the compound. XR11576 exhibited a similar pharmacokinetic profile in mice and rats after either i.v. or p.o. administration.In vivoXR11576 showed marked efficacy against a number of tumors including sensitive (H69/P) and multidrug-resistant (H69/LX4) small cell lung cancer and the relatively refractory MC26 and HT29 colon carcinomas following i.v. and p.o. administration. The efficacy of XR11576 was at least comparable to that of TAS-103, originally proposed as a dual inhibitor of topoisomerase I and II. These results suggest that XR11576 is a promising new antitumor agent with oral and i.v. activity, and warrants further development.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

NB1011, a novel anticancer agent, targets tumor cells expressing high levels of thymidylate synthase (TS). NB1011 is converted intracellularly to bromovinyldeoxyuridine monophosphate (BVdUMP) which competes with the natural substrate, deoxyuridine monophosphate, for binding to TS. Unlike inhibitors, NB1011 becomes a reversible substrate for TS catalysis. Thus, TS retains activity and converts BVdUMP into cytotoxic product(s).In vitrocytotoxicity studies demonstrate NB1011's preferential activity against tumor cells expressing elevated TS protein levels. Additionally, NB1011 has antitumor activityin vivo. To identify drugs which interact synergistically with NB1011, we screened 13 combinations of chemotherapeutic agents with NB1011 in human tumor and normal cells. Dipyridamole andp-nitrobenzylthioinosine (NBMPR), potent inhibitors of equilibrative nucleoside transport, synergized with NB1011 selectively against 5-fluorouracil (5-FU)-resistant H630R10 colon carcinoma cells [combination index (CI)=0.75 and 0.35] and Tomudex-resistant MCF7TDX breast carcinoma cells (CI=0.51 and 0.57), both TS overexpressing cell lines. These agents produced no synergy with NB1011 in Det551 and CCD18co normal cells (CI > 1.1) lacking TS overexpression. Dipyridamole potentiated NB1011's cytotoxicity in medium lacking nucleosides and bases, suggesting a non-salvage-dependent mechanism. We demonstrate that nucleoside transport inhibitors, dipyridamole and NBMPR, show promise for clinically efficacious combination with NB1011.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

We have studied the cytostatic effects of sodium phenylacetate (NaPA) in association with several substituted dextrans on human tumor melanoma 1205LU cells. We show that NaPA alone inhibits the growth of these cells (IC50= 3.9 mM) while a weak inhibitory effect appears at a concentration of 37 μM (10 μg/ml) for a dextran methyl carboxylate benzylamide (LS17-DMCB). The precursors of LS17-DMCB [T40 Dextran and carboxymethyl dextran (LS17-DMC)] did not affect the growth of 1205LU cells. To potentiate the inhibitory activity of NaPA at low concentrations (below 5.6 mM), we have tested NaPA and LS17-DMCB in physical mixture (association) or linked together covalently (this conjugate is termed ‘LS17–NaPaC’). We have observed an increase of the 1205LU cell growth inhibition effect with NaPA in association (IC501.8 mM). For a concentration of 5 mM of NaPA (free in the case of association or linked in the case of conjugate), the association with dextran derivative exhibits a 4.6-fold higher efficacy than with NaPA alone (9 versus 41% surviving fraction), while the conjugate is 1.3-fold smaller (52% growth inhibition). By performing isobologram analysis of the IC50data, we have shown a synergistic effect for a particular molar ratio of NaPA and LS17-DMCB (NaPA:LS17-DMCB = 0.35).

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The ONYX-015 virus is a mutated adenovirus that in theory selectively replicates and induces cytolysis in tumor cells lacking functional p53. The present study investigated whether ONYX-015 viral infection alone or in combination with conventional chemotherapeutic agents could significantly increase apoptosis in human colon cancer cell lines, regardless of p53 status, compared to untreated cells. A pair of colon cancer cell lines that differ only in their p53 status (RKO with wild-type p53 and RKOp53 with deficient p53) was tested. Two chemotherapeutic agents, 5-fluorouracil (5-FU) and CPT-11, were tested in combination with ONYX-015. Final concentrations of these agents corresponded to peak plasma levels achievable in patients. ONYX-015 concentration was 10 p.f.u./cell. In RKO and RKOp53 cell lines, ONYX-015 viral infection alone or in combination with 5-FU or CPT-11 induced a significant increase in apoptosis compared to chemotherapeutic agents alone, regardless of p53 status. Moreover, the combination of ONYX-015 and chemotherapeutics induced more apoptosis than chemotherapeutics alone in the two colon cancer cell lines independently of their p53 status. We conclude that ONYX-015 virus infection alone or in combination with 5-FU or CPT-11 induced apoptosis in human colon cancer cell lines, independently of p53 status.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Recombinant rIL-2 was reported to be able to decrease P-glycoprotein (P-gp) expression in cultured cells from human colon carcinoma. P-gp is considered an important factor in the control of Taxol®efflux from tumor cells. Based on the premise that Taxol pharmacokinetic parameters could be modified as a result of diminished P-gp expression induced by recombinant interleukin (rIL)-2 and that this might elicit an interaction between the two drugs, we evaluated the pharmacokinetics of a novel strategy combining i.p. immunotherapy with rIL-2 and a cytotoxic agent, Taxol. Mice were allocated to two groups treated with rIL-2 (15 μg×2/day from day 1 to 4) then Taxol (10 mg/kg i.p. day 5) or Taxol (10 mg/kg i.p.) alone (control group). The Taxol + rIL-2 combination provoked the development of ascites, presumably due to the presence of Cremophor EL in the Taxol preparation. Paclitaxel was measured in plasma and ascites by HPLC with UV detection. Paclitaxel pharmacokinetics were strongly modified by rIL-2 pretreatment. Compared to that observed in control mice, the apparent volume of distribution increased dramatically (Vd/F= 18.2 versus 4.1 l/kg) and the apparent plasma clearance decreased (Cl/F= 1.12 versus 1.66 l/h/kg). P-gp expression was determined in the liver, lung, intestine, brain and kidney in the two groups by immunodetection with the C219 anti-P-gp monoclonal antibody. A significant decrease in P-gp expression was observed in the intestine and in the brain in the rIL-2-pretreated mice as compared to controls. To study the functionality of P-gp, we compared digoxin (a model P-gp substrate) pharmacokinetics before and after pretreatment with rIL-2 (10 μg×2/day from day 1 to 4), after a single 1 μg oral dose of digoxin used to quantify P-gp activity. Results showed a decrease in oral digoxin clearance after rIL-2 pretreatment indicating modified P-gp activity. We conclude that rIL-2 pretreatment is able to decrease P-gp activity and paclitaxel metabolismin vivo. This is the first study to demonstrate a decrease in P-gp activity and expression in organs such as the brainin vivo. A novel strategy combining immunotherapy with rIL-2 and a cytotoxic agent could potentially improve clinical results, particularly in brain cancer.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Proliferator-activated receptor&ggr;(PPAR&ggr;) is a nuclear receptor, which mainly associates with adipogenesis, but also appears to facilitate cell differentiation or apoptosis in certain malignant cells. This apoptosis induction by PPAR&ggr;is increased by co-stimulation with tumor necrosis factor (TNF)-&agr;-related apoptosis-inducing ligand (TRAIL), a member of the TNF family. In this study, we investigated the effect of PPAR&ggr;on Fas-mediated apoptosis in hepatocellular carcinoma (HCC) cell lines. PPAR&ggr;was expressed on all seven HCC cell lines and located in their nuclei. 15-Deoxy-&Dgr;-12,14-prostaglandin J2(15d- PGJ2), a PPAR&ggr;ligand, inhibited cellular proliferation in HepG2, SK-Hep1 or HLE cells, unlike pioglitazone, another PPAR&ggr;ligand, which did not have a significant influence on proliferation of these cells. However, 15d-PGJ2facilitated Fas-mediated HCC apoptosis that could not be induced by Fas alone. These results suggest that PPAR&ggr;can augment TNF-family-induced apoptosis.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Anthracyclines and taxanes are to date the most active cytotoxic agents in the treatment of breast cancer, and a combination of these is therefore considered to result in the highest response rates in the neoadjuvant, as well as in palliative treatment. These two phase II studies aimed to evaluate the feasibility, toxicity and activity of a cytostatic regimen combining epidoxorubicin and docetaxel in outpatient patients suffering from breast cancer. In total, 104 consecutive patients were enrolled in these prospective clinical trials. The chemotherapeutic regimen consisted of epidoxorubicin [75 mg/m2body surface area (BSA)] and docetaxel (75 mg/m2BSA) on day 1 accompanied by the administration of granulocyte colony stimulating factor on days 3–10, repeated every 3 weeks (ED+G). Sixty-six patients received ED+G as neoadjuvant and 38 patients as palliative treatment, respectively. Patients received a total of 566 cycles (median: 6 cycles, range: 2–11 cycles) of this therapeutic regimen. Outpatient ED+G was well tolerated. A major response to preoperative ED+G could be demonstrated in 54 of 66 patients (82%) and in 22 of 38 palliative treated patients (58%). We conclude that outpatient ED+G is safe in the neoadjuvant and palliative treatment of patients suffering from breast cancer by showing a favorable side effect and activity profile. Thus, this regimen can be considered for further clinical trials.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Thymidine synthase (TS) is a key enzyme in the synthesis of pyrimidine in thede novopathway of DNA synthesis and a major target of 5-fluorouracil (5-FU), but the implications of TS regarding human pancreatic cancer have not been reported. We assessed the expression of TS in invasive ductal carcinoma (IDC) of the pancreas by immunostaining and evaluated its clinicopathological significance, especially its implications regarding the efficacy of chemotherapy with 5-FU or its derivatives. The expression of TS in the nuclei of pancreatic cancer cells in 72 primary lesions of resectable IDC and 30 distant metastases of unresectable IDC was examined by immunostaining using anti-TS polyclonal antibody and immunoreactivity was classified into three categories: negative (−), low (+) and high (2+). High TS immunoreactivity was detected in 43% (31 of 72) of the primary lesions of the resectable IDCs and in 47% (18 of 38) of the metastatic lesions of the unresectable IDCs. The high TS in primary lesions showed a significantly inverse correlation with the level of nodal involvement. High TS immunoreactivity had a significant influence on the outcome of patients with resectable IDC and the rate of survival of the high TS immunoreactivity group was significantly higher than that of the negative or low reactivity groups, although high TS immunoreactivity did not have a significant influence on survival of the patients with unresectable IDC. The implications of TS immunoreactivity regarding the efficacy of 5-FU-based adjuvant chemotherapy (ACT) was also assessed. The high TS immunoreactivity group showed significantly better survival in both the patients who received ACT and those who were treated by surgery alone, in the resectable IDC among patients with resectable IDC. In cases of unresectable IDC, there were no differences in survival between the high and low TS groups among the patients who received ACT and those who were treated by surgery. In conclusion, high TS immunoreactivity was found to be cogent in predicting the prognosis of patients with pancreatic IDC, but its implications regarding the efficacy of 5-FU-based ACT are still unclear.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Topotecan stabilizes the topoisomerase I (Topo I) cleavable complex. We measured Topo I levels in white blood cells of patients with ovarian cancer treated with topotecan. Topotecan was given i.v. daily ×5 q 3 weeks in combination with paclitaxel (1 day before topotecan) and cisplatin (just prior topotecan). Our aim was to correlate Topo I levels to pharmacokinetics and toxicity. Topo I levels were determined using Western blotting and were expressed relative to the Topo I level present in 10 μg cell lysate of the human IGROV1 ovarian cancer cell line. We found no correlation between Topo I levels and (non-)hematological toxicity. Topo I levels after the fifth topotecan infusion were significantly negatively correlated with the AUC of topotecan (R =−0.64,p=0.026), in contrast with Topo I levels prior to (R =−0.25,p=0.4) and after (R =−0.30,p=0.3) the first topotecan infusion. Topo I levels after the fifth topotecan infusion (48±27%, mean±SD) were higher than Topo I levels prior to and after the first topotecan infusion (3.0±4.7 and 2.7±3.6%, respectively) (p=0.001). In conclusion, we detected a significant inverse correlation between Topo I level and topotecan AUC at day 5, and we found increasing Topo I levels during a daily ×5 schedule of treatment with topotecan.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID