摘要:

The bryostatins are a group of novel macrocyclic lactones derived from the marine bryozoan,Bugula neritina.In vitroevidence indicates that their main mechanism of action is modulation of protein kinase C (PKC) activity. Phase I studies suggested significant antineoplastic activity against several tumor types and defined the main dose-limiting toxicity as myalgia. Bryostatin-1 has subsequently been investigated extensively in phase II clinical trials as a single agent, although trial design has been hampered by lack of human pharmacokinetic data. Results have been generally disappointing butin vitroand animal data suggests an important role for bryostatin-1 in combination with cytotoxic agents. Preliminary results of phase I studies support these observations but further work needs to be done to define the future role of the bryostatins in the clinic.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Gemtuzumab Ozogamicin (GO, CMA-676) is a monoclonal antibody against the cellular surface antigen CD33 conjugated with the cytotoxic antibiotic calicheamicin. In the beginning of 2000 it obtained US Food and Drug Administration approval for the treatment of refractory acute myeloid leukemia (AML) expressing CD33 in patients older than 60 years who are not candidates for other chemotherapy. After ligation with the CD33 on the cell surface, GO is internalized and hydrolyzed. Its two components are released into the cytoplasm and calicheamicin enters the nucleus where it associates with the DNA, causing double helix breaks and finally cell death. GO is in general well tolerated. The most frequent adverse effect observed is myelotoxicity, with prolonged neutropenia and thrombocytopenia. Veno-occlusive disease of the liver is a less frequent but severe adverse effect. A phase II study points towards a percentage of overall hematologic response around 30% in the setting of refractory or relapsed disease. Future phase III trials will show the most suitable place of GO in the treatment of AML.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Introducing a cytokine receptor as a sensitizer into cancer cells offers a unique opportunity for receptor-targeted cancer therapy. It has been shown that transfection of the tumor necrosis factor (TNF) receptor gene in cancer cells or exposing cancer cells to certain reagents which increase expression of TNF receptors results in enhancement of the cytotoxic effect of TNF. In addition, the literature suggests that Fas/CD95-mediated apoptotic tumor cell killing is augmented by gene transfer of Fas into cancer cells or treatment of cells with agents like cisplatin and interferon (IFN)-&ggr;. In contrast to these approaches, we have discovered a new approach to cancer therapy; wherein introduction of a cytokine receptor chain into cancer cells sensitizes them to receptor-directed cytotoxins. We have demonstrated that when interleukin (IL)-13 receptor (IL-13R)&agr;2 chain, one of the two known IL-13 binding proteins, is introduced into cancer cells that do not express this chain the cells acquire extreme sensitivity to a chimeric fusion cytotoxin composed of IL-13 and a mutated form ofPseudomonasexotoxin (IL13-PE). Cells that do not express this chain or express low levels show limited sensitivity to IL13-PE. Acquisition of sensitivity to IL13-PE was observed bothin vitroandin vivowhen IL-13R&agr;2-transfected human tumor cells were implanted in immunodeficient animals followed by systemic or regional IL13-PE therapy. Our third generation experiments suggest that this approach is feasible for clinical situations as intratumor administration of plasmid carrying the IL-13R&agr;2 chain gene sensitized these tumors to systemic or regional IL13-PE therapy. This unique approach comprising gene transfer of cytokine receptor chain and receptor-targeted cytotoxin administration represents a novel strategy for cancer therapy.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Trophoblast injury may be one of the possible causes of fetal distress associated with chemotherapy administered during pregnancy. The purpose of this study was to investigate theex vivochemosensitivity of normal trophoblasts (NTB) against commonly used antineoplastic agents. Using the newly developedex vivoATP-based trophoblast assay (ATP-TBA), 31 NTB freshly sampled from human placentas (gestational week 7–42) were tested against dactinomycin (Act-D), 5-fluorouracil (5-FU), 4-OOH-cyclophosphamide (4-HC), vincristine (VCR) and methotrexate (MTX) alone or in combination with calcium folate (LV). All agents were studied at concentrations relevant to clinical dosages normally used for chemotherapy of solid neoplasms. Of 31 samples studied with the ATP-TBA, 20 (65%) were evaluable. VCR, Act-D and 4-HC were the most active drugs with 55, 45 and 45% of samples respondingex vivo. Antimetabolites were less active, producingex vivoresponse rates of 25 (MTX) and 20% (5-FU), respectively. MTX activity was largely neutralized by adding LV. The chemosensitivity of NTB showed considerable inter-individual variations and did not decrease with increasing gestational age. We therefore conclude that NTB of any gestational age exhibit considerableex vivosensitivity against common anticancer agents which is comparable to that observed for various solid tumors. The ATP-TBA may be helpful in planning future trials with both single agents and drug combinations in order to standardize and optimize chemotherapy during pregnancy.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Topotecan (TPT), a topoisomerase I inhibitor, is presently undergoing clinical evaluation worldwide. Previous studies have shown that entrapping TPT within multi-lamellar vesicle liposome can stabilize the lactone moiety, which is structurally important for biological activity. However, low drug:lipid ratios due to the amphipathic character and small entrapment volume in the unilamellar vesicle limits the development of pharmaceutically acceptable liposomal formulation. With an aim to improve on this drawback, we herein describe a method that utilizes the ammonium sulfate gradient to entrap TPT into liposomes. By this method, the encapsulation efficiency was over 90% and a drug:lipid molar ratio as high as 1:5.4 was reached. In comparison with free drug, liposome-encapsulated TPT is more stable in physiological conditions and shows higherin vitrocytotoxicity. Because of increased blood circulation time, the initial plasma concentration and area under the plasma concentration of liposomal drugs were 14 and 40 times, respectively, of those of free drug. Furthermore, liposome encapsulation enhanced the antitumor activity of TPT in syngeneic murine C-26 and human HTB-9 xenograft modelsin vivo. At a dose of 5 mg/kg, the tumor growth delay of liposomal formulation was significantly than that of free TPT. Based on these results, we believe that this liposomal TPT formulation is worthy of further clinical study.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

For advanced colorectal carcinoma, two new drugs, raltitrexed (TOM) and oxaliplatin (L-OHP), have recently shown interesting results. Preclinical and clinical studies suggest that this combination, because of its favorable toxicity profile, high response rate and convenient schedule of administration, can be administered successfully in this disease. In our phase II study, 37 non pre-treated patients with metastatic colorectal carcinoma were treated with TOM (3 mg/m2) and L-OHP (130 mg/m2) every 3 weeks. In total, 222 cycles were administered; all patients received at least 2 cycles (median 6, range 2–8). There were two complete and 14 partial responses for an overall response rate of 43% (95% CI 27–69%). The median time to response was 2.5 months (range 2–4) and the median duration was 10.3 months (range 5–18). Twelve of the 23 (52%) patients with symptomatic colorectal cancer were classified as clinical benefit responders for at least 4 weeks during the study period. Treatment was well tolerated, and both acute, essentially hematologic, and cumulative hepatic and neurologic toxicities were manageable and reversible. Response rate and toxic effects observed during this study warrant additional studies comparing this TOM–L-OHP regimen with CPT-11 and/or capacitebine-containing regimens in metastatic colorectal carcinoma.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Modulation of protein kinase C (PKC) activity has been demonstrated to either prevent or enhance drug-induced apoptosis in various tissue types. We tested four novel modulators of PKC activity in comparison to the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) for the capability to affect differentiation, cell cycle progression and apoptosis in the human myeloid leukemia cell lines U937 and HL-60. Farnesyl thiotriazole (FTT) andN-(n-heptyl)-5-chloro-1-naphthalenesulfonamide (SC-10) are both direct activators of PKC, whereas 6-(2-(4-[(4-fluorophe-nyl)phenylmethylene]-1-piperidinyl)ethyl)-7-methyl–5H-thiazolo[3,2-a]pyrimidin-5-one (R59022) and [3-[2-[4-(bis-(4-fluorophenyl)methylene]piperidin-1-yl)ethyl]-2,3-dihydro-2-thioxo-4(1H)-quin-azolinone (R59949) are diacyl glycerol kinase inhibitors that activate PKC by enhancing the levels of the endogenous ligand diacyl glycerol. U937 cells displayed a slight reduction in the number of cells in G2/M cell cycle phase after exposure to FTT, SC-10, R59022 and R59949, respectively. In contrast, HL-60 cells demonstrated a largely unaltered cell cycle distribution. Whereas TPA treatment resulted in a strong induction of p21WAF/CIP1, c-Fos and c-Jun levels, neither one of the novel PKC activators altered expression of these proteins. Consequently, we tested the ability of the activators to cause membrane translocation of PKC. While TPA treatment resulted in translocation of the PKC isoforms&agr;,&dgr;andϵ, SC-10 and FTT failed to induce alterations in the PKC content of the membrane and cytosolic fractions, respectively. Expression of the&bgr;2-integrin CD11c that is induced during TPA-mediated differentiation remained unaltered after exposure to SC-10 and was partly reduced after treatment with FTT. To further investigate the effect of these activators upon apoptosis in leukemic cells, HL-60 and U937 cells were treated with 1-&bgr;-d-arabinofuranosylcytosine (Ara-C) or etoposide (VP-16). Whereas TPA strongly reduced apoptosis in Ara-C- or VP-16-treated U937 cells, little if any reduction was observed after pretreatment with either FTT, SC-10, R59022 or R59949, respectively, in these cells. In contrast, TPA enhanced apoptosis in Ara-C- or VP-16-treated HL-60 cells. Interestingly, FTT and SC-10 demonstrated a protective effect in Ara-C-treated HL-60 cells. Taken together, these data suggest that the novel PKC activators FTT, SC-10, R59022 and R59949 exhibit modest biological effects upon leukemic blast cells, and are not capable of enhancing the apoptotic response of these cells to cytotoxic drugs.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

CHS 828, a pyridyl cyanoguanidine, is a new drug candidate now in phase I/II trials, that has shown promising anticancer activity in experimental tumor models and primary cultures of cancer cells from patients. In this study the fluorometric microculture cytotoxicity assay was used for evaluation of CHS 828 in primary cell cultures from children with acute leukemia. The activity of and interaction with the standard drugs, doxorubicin, melphalan, etoposide and cytosine arabinoside (Ara-C), were also assessed. Samples from 65 patients, 42 with acute lymphocytic leukemia (ALL) and 23 with acute myelocytic leukemia (AML) were tested with 72-h continuous drug exposure. There was 50% cell kill at very low CHS 828 concentrations; median IC50was 0.01 μM in ALL and 0.03 in AML samples (NS) with large interindividual variability in both groups. ALL samples were significantly more sensitive than AML samples to melphalan, doxorubicin and etoposide, but not to Ara-C. In AML samples, combinations between CHS 828 and each of the four standard drugs resulted in significantly lower cell survival than either drug alone. This was also observed in ALL samples, except for Ara-C. Using the additive interaction model, CHS 828 showed a synergistic effect with melphalan in 67%, doxorubicin in 47%, etoposide in 38% and Ara-C in 14% of AML samples. In most ALL samples subadditive effects were found. Further exploration of CHS 828 in childhood leukemia is warranted, especially in AML.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

We have previously shown that C-CAM1-based gene therapy effectively suppressed prostate tumor growth in nude mice xenograft models. In this study, we examined the effects of combining C-CAM1-based therapy and TNP-470, a potent angiogenesis inhibitor, on prostate cancer in a xenografted tumor model. The direct cytotoxic effects of Ad-C-CAM1 (recombinant adenovirus containing C-CAM1 cDNA) and TNP-470 on DU145 cellsin vitrowere determined by microculture tetrazolium assay. Thein vivoantitumor effects of either agent alone were studied in a DU145 xenografted tumor model. Cells were infected with Ad-C-CAM1 or the control virus at multiplicities of infection (m.o.i.) of 5 or 10 and then inoculated onto nude mice 48 h later. TNP-470 (0, 17 or 35 mg/kg) was given 15, 17 and 19 days after inoculation. Combined treatmentsin vivowere carried out to determine whether there were synergistic antitumor effects. Both Ad-C-CAM1 and the control virus were minimally toxic to DU145in vitro. There was evident dose-dependent suppression of xenografted tumor growth by either Ad-C-CAM1 or TNP-470. By the median-effect analysis, combination of the two agents generated strong synergistic antitumor effects as shown by marked tumor suppression as compared to either treatment alone. The novel strategy may have clinical implications for the treatment of prostate cancer.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Elucidation of the mechanisms of action of the thiol and alkylating agents on normal cells requires the knowledge of their cell cycle phase specificity in terms of their ability to induce apoptosis. The effects ofS-2-/3-aminopropylamino/ethyl phosphorothioic acid (WR-2721, Amifostine) and cyclophosphamide (CP) on apoptosis and cell cycle progression were assessed in the mouse bone marrow. Adult male Swiss mice were treated with WR-2721, at a dose of 400 mg/kg body weight, and/or CP, at a dose of 200 mg/kg body weight. Application of the laser scanning cytometry APO-BRDU assay, a two-color staining method for labeling of DNA breaks and cellular DNA, allowed an identification of apoptotic and non-apoptotic cells, and their position with respect to their cell cycle phase. Temporary alterations in the number of apoptotic cells and also all bone marrow cells, including apoptotic and non-apoptotic ones, were determined throughout the 240-h period after treatment of mice with WR-2721 and/or CP. These drugs, given alone, affected apoptotic cell death and caused deregulation of the cell cycle in the bone marrow. WR-2721, applied 30 min prior to CP administration, resulted in a suppressing effect on apoptosis and the cell cycle perturbation triggered in normal bone marrow cells by the alkylating drug. The patterns of changes in the frequency of apoptotic cells and the number of apoptotic and non-apoptotic bone marrow cells, observed in all phases of the cell cycle, were dependent on the agent(s) given and the time interval after WR-2721 and/or CP administration.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID