摘要:

Kaposi's sarcoma (KS) is an angioproliferative disease of multifactorial origin arising in different clinic-epidemiologic forms, which show the same histopathological features. It generally starts as a hyperplastic reactive-inflammatory and angiogenic process, which may evolve into monomorphic nodules of KS cells that can be clonal (late-stage lesions) and resemble a true sarcoma. Infection with the human herpesvirus 8, cytokine- and angiogenic factor-induced growth together with an immuno-dysregulated state represent fundamental conditions for the development of this tumor. Several local therapies are used to eradicate early and confined skin lesions, whereas widely disseminated, progressive or symptomatic disease requires a more aggressive treatment. Although different chemotherapeutic agents have been used to treat aggressive KS, the growing understanding of the pathogenetic factors participating in KS development has provided a strong rationale for using less- or non-cytotoxic agents that block the mechanisms involved in KS pathogenesis. The angiogenic nature of KS makes it particularly suitable for using therapies based on anti-angiogenic agents. Of note on this goal, recent studies indicate that the highly active anti-retroviral therapy, including at least one human immunodeficiency virus (HIV) protease inhibitor (PI), is associated with a dramatic decrease in the incidence of AIDS-KS and with a regression of KS in treated individuals. Consistent with this, results from preclinical studies indicate that PIs have potent and direct anti-angiogenic and anti-KS activities, suggesting that they should be further investigated, alone or combined with other therapies, as a novel treatment for KS in both HIV seropositive or seronegative individuals.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Cell cycle regulation and cell growth are interesting targets in the search for new antitumor agents as these processes are highly disturbed in malignant cells. E7070 is a novel synthetic sulfon-amide that targets the G1phase of the cell cycle and is currently in clinical development for the treatment of solid tumors. The potential antitumor activity of the compound was discovered through optimization of the structure–activity relationships of a series of sulfonamide structures. E7070 causes a blockade in the G1/S transition through inhibition of the activation of both cyclin-dependent kinase 2 and cyclin E. Preclinical studies with E7070 showed activity in multiple tumor types, most prominently in colon and lung cancer. A phase I clinical program was conducted with E7070 evaluating different treatment regimens. Dose-limiting toxicities were hematological, including neutropenia and thrombocytopenia. Preliminary results of phase II studies demonstrated limited antitumor activity following treatment with E7070 as single agent in heavily pretreated patients with non-small cell lung and colon cancer. Studies evaluating the activity of E7070 in combination with other chemotherapeutic agents are being conducted.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Irinotecan (CPT-11) has been shown to prolong survival and improve quality of life in comparison to best supportive care in colorectal cancer patients with pretreatment of bolus 5-fluorouracil (5-FU). After first-line 24-h high-dose (HD) 5-FU/folinic acid (FA) an objective response rate of 11% with 3-weekly CPT-11 350 mg/m2was reported. In the present study we investigated weekly CPT-11 in combination with 24-h HD-5-FU/FA as second-line treatment after prior exposure to 24-h HD-5-FU. Synergy between 5-FU and CPT-11 is the rationale to combine both substances for second-line therapy in order to overcome resistance to 5-FU. Thirty-five patients were recruited in a single institution to receive 6 × weekly CPT-11 80 mg/m2, FA 200 mg/m2and 24-h HD-5-FU 2000 mg/m2. Treatment was repeated on day 57. Patient characteristics: M/F=20/15, median WHO performance status 1, range (0–2). Thirty-four patients were evaluable for response: partial response 17% and no change 40%. Median time to progression and overall survival were 3.3 and 8.4 months, respectively. All patients were evaluable for toxicity analysis (National Cancer Institute Common Toxicity Criteria grade 3): leukocytopenia 3%, diarrhea 12% and vomiting/nausea 6%. Of the assigned doses, a median 100% of 5-FU and 92% of CPT-11 were administered during the first cycle of chemotherapy. We conclude that weekly CPT-11 and HD-5-FU/FA is an active and safe combination chemotherapy resulting in response rates in the upper range of other CPT-11-based second-line regimen. The toxicity profile in our series compared to 3-weekly CPT-11 seems favorable.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Continuous 5-fluorouracil (5-FU) infusion during radiation therapy is superior to the application of bolus 5-FU schedules. As an oral therapy, that provides prolonged fluoropyrimidine exposure, uracil and Tegafur (UFT) plus leucovorin (LV) has shown favorable activity with only moderate toxicity in colorectal cancer. The present study was designed to evaluate the safety of UFT+LV combined with pelvic radiation to determine the maximum-tolerated dose (MTD) in recurrent rectal cancer. Patients with recurrent rectal cancer received escalating doses of UFT (starting at 250 mg/m2/day with 50 mg/m2/day increments between consecutive cohorts) and fixed doses of LV (90 mg). The UFT+LV combination was given 5 days per week simultaneously to a 5-week course of irradiation up to a total dose of 50.4 Gy, 1.8 Gy daily fractions followed by a boost of 5.4 or 9.0 Gy to the gross tumor volume. Nineteen patients were treated and 14 received the full chemotherapy with delivery of all planned radiotherapy. The MTD of UFT was 400 mg/m2/day due to the occurrence of dose-limiting diarrhea and emesis. Toxicities were mild and manageable on the lower dose levels. Treatment was feasible mainly on an outpatient base. We conclude that combined chemoradiation with oral UFT+LV is feasible and well tolerated for recurrent rectal cancer patients undergoing pelvic radiation. The safety profile appears comparable to that of i.v. dosing without requiring any i.v. port systems. The recommended doses for further phase II chemoradiation trials are 350 mg/m2/day UFT+90 mg LV.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Microtubulin binding agents such as docetaxel have significant preclinical and clinical activity in the treatment of hormone-refractory prostate cancer. We have previously used median-effect analysisin vitroto define both synergistic and antagonistic drug combinations which may be of value in management of human disease. These studies extend our findings in defined prostate cancer cell lines. A semi-automated microtiter culture system was used. Docetaxel was combined with 18 other agents, incubated with DU 145, LnCaP or PC 3 prostate cancer cell lines for 72 h and the cells then incubated with MTT to determine cytotoxic effect. Both doublet and triplet combinations were examined. Synergy and antagonism as measured by the combination index were determined for each combination. The non-mutually exclusive criterion was applied. Docetaxel demonstrated cytotoxic additive effects or synergy withcis-retinoic acid, cyclosporin A and vinorelbine in all three cell lines. Docetaxel combined with either epirubicin or doxorubicin displayed cytotoxic synergistic effects in hormone-refractory DU 145 and PC 3 cell lines. In contrast, drugs which have been combined clinically to treat hormone-refractory prostate cancer, i.e. cisplatin, carboplatin or etoposide, were antagonistic when combined with docetaxel. We conclude that combinations of docetaxel with eithercis-retinoic acid or vinorelbine may offer an enhanced cytotoxic effect in the management of hormone-refractory prostate cancer and need to be evaluated for therapeutic effect. The combination of docetaxel with an anthracycline was also synergistic in the two hormone-refractory cell lines, DU 145 and PC3, thus suggesting a potential role in advanced disease after endocrine failure. Combinations of docetaxel with platinum or etoposide may lead to subadditive effects in treatment.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Cyclooxygenase (COX)-2 inhibitors that belong to non-steroid anti-inflammatory drug family have been shown to have an apoptosis-inducing effect on neoplastic cells. In the present study the effect of nimesulide (NIM), a specific COX-2 inhibitor, on apoptosis and interactions between BCL-2 family death promoters BAX and BID and BAX and VDAC-1 were examined in human colon adenocarcinoma COLO 205 cells. Laser scanning cytometry was applied for the measurement of expression and aggregation of apoptosis-related proteins and quantitative analysis of NIM-induced apoptosis. Double-staining immunoconfocal and immunoelectron microscopy were used for subcellular colocalization of examined proteins. NIM induced apoptosis of COLO 205 cells in a dose-dependent manner. This was accompanied by: (1) a decrease in intracellular prostaglandin (PG) E2content; (2) subcellular redistribution and aggregation of BAX and BID on organellar membranes and within the nucleus; (3) colocalization of BAX with BID and BAX with VDAC-1 on organelles; and (4) survival of cells with the highest BCL-2 aggregation. A similar pattern of subcellular redistribution and colocalization of BAX with BID and BAX with VDAC-1 suggests that BAX (in association with BID) controls the function of VDAC-1 and its permeability for apoptogenic factors released from mitochondria of COLO 205 cells stimulated to apoptosis with NIM.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Imexon is a new antitumor agent with high activity in multiple myeloma. This drug induces apoptosis, oxidative stress and mitochondrial alterations. However, it was unknown whether imexon activates an intrinsic apoptotic pathway that is associated with activation of caspase-9 or an extrinsic pathway that is induced by receptor-mediated signals such as Fas ligand characterized by caspase-8 activation. In addition, we wanted to investigate the effect of imexon on Bcl-2 family proteins. In RPMI8226 myeloma cells, imexon activated caspase-9 and -3 in a time- and concentration-dependent manner. In contrast, cleavage of procaspase-8 was observed late and only after exposure to very high concentrations of imexon. Confocal microscopy confirmed that caspase-3 is also activated after treatment with imexon. High imexon concentrations activated caspase-3 and -9 at 12 h, while caspase-8 activation occurred only at 48 h. Imexon cytotoxicity was unchanged in three RPMI8226 cell lines with different levels (low, medium and high) of FAS expression. Similarly, the levels of Bcl-2, Bax and Bcl-xLwere unchanged in imexon-treated cells. However, Bcl-xLwas translocated to the mitochondria. These data suggest that imexon-induced oxidation activates the intrinsic or mitochondrial pathway of apoptosis, involving cytochromecrelease and activation of caspase-9 and -3.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Efforts have been made to reduce the undesirable side effects of cisplatin, mainly nephro- and neurotoxicity, but their reduction is usually accompanied by a concomitant inhibition of antitumor activity. The local anesthetic procaine hydrochloride (P.HCl) improves the therapeutic index of cisplatin not only by the reduction of its nephro- and hemotoxicity, but also by an increase of its antitumor activity. We therefore investigated the effects of a combined treatment of cisplatin and P.HCl on rat kidneys and compared this to kidneys from rats treated with a toxic dose of cisplatin or P.HCl alone. Treatment with a saline solution was used as control. Dehydrogenase activities [succinate dehydrogenase (SDH) and NADPH diaphorase reaction demonstrating nitric oxide synthase (NOS/NADPHd)] and phosphatase activities [K+p-nitrophenyl phosphatase (K+pNPPase), alkaline phosphatase (AlPase) and acid phosphatase (AcPase)] were studied on cryostatic sections of kidneys from controls and treated rats. Evidence of heavy morphological damage and altered AlPase and AcPase activities induced by cisplatin were observed in the S3 segment of the proximal tubules. In addition, SDH and K+pNPPase activities showed some changes in the distal tubule cells. The NOS/NADPHd activity in macula densa was drastically reduced. Combined treatment of cisplatin and P.HCl greatly attenuated morphological alterations of the rat kidney and reduced the changes in enzyme activities, except for NOS/NADPHd activity, compared to the cisplatin-treated group of animals. The study indicates that, in cisplatin-induced nephrotoxicity, a significant role is played by enzyme activities, in particular K+pNPPase and NOS/NADPHd, and that P.HCl can mitigate the nephrotoxicity of cisplatin, possibly by influencing some enzyme activities involved in important renal metabolic pathways.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

STI571 is a specific ABL family tyrosine kinases inhibitor approved for treatment of leukemias. It can differentially modulate the action of other antileukemic drugs. We have recently shown that deregulation of the mechanisms of DNA damage and repair in BCR/ABL-positive cells may be involved in drug resistance of these cells, and thus determine the response of cancer cells to therapy. In the present work we investigated DNA damage and repair induced by idarubicin in the presence of STI571 and amifostine, a normal cell protector, in the BCR/ABL fusion tyrosine kinase-expressing cell line. Amifostine increased the viability of both kinds of cells in the absence of STI571, but had no effect in the presence of the inhibitor. STI571 did not change the response of both BCR/ABL-expressing cells and their control counterparts to idarubicin in terms of DNA damage and repair. However, the presence of amifostine modulated the response of the cells. In the absence of STI571 amifostine decreased the DNA-damaging effect of idarubicin in normal cells and increased it in BCR/ABL-positive cells. STI571 at 2 μM abolished the protective effect of amifostine against idarubicin in normal cells and diminished the magnitude of the amifostine-induce increase in cancer cells. These results suggest that amifostine should be applied with special caution in idarubicin-based chemotherapies of BCR/ABL-positive leukemias involving STI571 inhibitor.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Cryptophycin (CP)-52, a synthetic analog of CP-1, possesses potent and selective antiproliferative activity against human solid tumors bothin vitroandin vivo. Based on an algorithm developed in this laboratory using HCT-116 human colon adenocarcinoma cells, CP-52 exhibited a time- and concentration-dependent antiproliferative effect in thein vitroclonogenic assay. Inhibition of both DNA and RNA synthesis was observed in the absence of any effect on protein synthesis following a 24-h exposure to CP-52, at a time when proliferating cells were arrested in the G2/M phase of the cell cycle. In summary, we interpret these data to indicate that the selective inhibition of DNA synthesis may be a major causative factor responsible for the antiproliferative activity of CP-52 and subsequent G2/M arrest.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID