摘要:

Recently, it has been demonstrated that a number of novel thalidomide analogs possess anti-cancer properties due to their T cell co-stimulatory, anti-angiogenic and/or anti-inflammatory effects. Based on such effects, a class of thalidomide analogs known as Immunomodulatory Drugs (IMiDs™) have recently entered into phase I clinical trials for the treatment of a number of cancers. The lead IMiD CC-5013 (referred to clinically as REVIMID™) is now entering phase III clinical trials for multiple myeloma and metastatic melanoma, while CC-4047 (ACTIMID™) is currently under investigation in phase I/II and II trials for multiple myeloma and prostate cancer, respectively. The other group of compounds, classified as Selective Cytokine Inhibitory Drugs (SelCIDs™), do not co-stimulate T cells, but have anti-inflammatory and anti-angiogenic properties. Moreover, a subset of SelCIDs has been found to posses direct anti-tumor activity bothin vitroandin vivo. This minireview highlights the various mechanisms of action associated with these compounds and their subsequent clinical development. The enhanced efficacy and lower side-effect profiles of the analogs in comparison to thalidomide make the use of these agents very attractive as novel anti-cancer agents.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

No effective treatment currently exists for metastatic uveal melanoma. However, recent results obtained by an ATP-based tumor chemosensitivity assay have shown consistent activity of treosulfan+gemcitabine in up to 80% of tumor specimens tested. In this study we describe the first clinical results observed with this drug combination at different European centers in patients with metastatic uveal melanoma. Clinical case series of patients with metastatic uveal melanoma were treated with treosulfan+gemcitabine at seven different centers. Fourteen patients, 13 previously untreated and one pretreated with chemoimmunotherapy, were included in the study. Patients received treosulfan+gemcitabine in four different dose regimens. The response rates, progression-free and overall survival, and toxicity were evaluated. The analysis of 14 patients revealed one complete response, three partial responses and a stable disease in eight cases. The objective response rate was 28.6%, the median overall survival was 61 weeks [95% confidence interval (CI) 54–133 weeks], the progression-free survival was 28.5 weeks (95% CI 13–62 weeks) and the 1-year survival rate was 80%. The drugs were well tolerated. The most common side-effects were leuko- and thrombocytopenia. These preliminary results suggest potential therapeutic benefit of treosulfan+gemcitabine treatment in metastatic uveal melanoma and warrant further controlled studies.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The long-term results for patients with recurrent ovarian cancer (ROC) are poor. There is a need to optimize treatment strategies to improve outcome by avoiding ineffective regimens which are often associated with exacerbated side-effects. Individualized chemotherapy regimens guided by a chemosensitivity assay (ATP-tumor chemosensitivity assay) have already been used successfully to direct chemotherapy. Taking the results of this assay into account, application of drug combinations appears more advisable. Here we present a systematic evaluation of toxicities seen with individualized chemotherapy for ROC. A total of 62 patients who received 314 cycles of antineoplastic therapies were evaluated. Three single agents (topotecan, paclitaxel and gemcitabine) and five combinations (cisplatin/gemcitabine, carbopatin/gemcitabine, gemcitabine/treosulfan, mitoxantrone/paclitaxel and carboplatin/paclitaxel) were examined. With respect to myelotoxicity, most single agents except topotecan revealed favorable results in comparison to drug combinations. However, this observation lacks statistical significance. Generally, severe myelosuppression was rare. The highest incidence of leukopenia was seen in regimens with mitoxantrone/paclitaxel or gemcitabine/treosulfan, respectively. Thrombocytopenia accompanied most commonly a topotecan therapy. In the present study combination regimens tend to be more toxic than monotherapies. When response rates are comparable, empirically chosen treatment combination therapies should only be practiced in carefully planned clinical studies.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The combination of platinum and paclitaxel is the standard treatment of advanced ovarian carcinoma; however, recent studies have questioned the actual role of the combination as compared to either of the two agents alone. We report an open-label, two-center, phase II study of upfront paclitaxel for patients with histological diagnosis of stage III ovarian carcinoma. Treatment consisted of paclitaxel at 175 mg/m2administered in a 3-h infusion every 21 days. Response was evaluated after the third course by either laparoscopy or exploratory laparotomy. Patients with stable or progressive disease discontinued treatment, whereas responding patients continued treatment until a maximum of six courses. Response, toxicity, time to progression (TTP) and survival were evaluated. From November 1993 to December 1995, 30 patients were accrued. All patients underwent primary cytoreduction; 17 (57%) and 13 (43%) patients had residual tumors <2 and >2 cm, respectively. Of 27 patients evaluable, objective responses were seen in 18 (66.4%) (95% CI 49.5–83.2)—12 complete (45%) and six partial (22%). Four patients had stable disease (15%) and five (18%) patients progressed. A total of 149 courses were administered to 30 patients, median 4 (range 1–6). Grade 3/4 neutropenia was seen in 13% of courses, peripheral neuropathy, myalgia and arthralgia were frequent, but transitory and relieved with analgesics. At a median follow-up time of 44.5 months (0–99) the TTP and median survival were 16.6 and 43.1 months, respectively. We conclude that single-agent paclitaxel is an effective and well-tolerated first-line treatment for advanced ovarian carcinoma.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Our aim was to develop a population pharmacokinetic model for irofulven and to assess covariates that might affect irofulven pharmacokinetics. Irofulven was administered by 5- or 30-min i.v. infusion to cancer patients during a phase I study. Blood samples were collected over 4 h. Plasma samples were analyzed to quantitate irofulven by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using a non-linear mixed effects modeling program, MP2. Fifty-nine patients were available for pharmacokinetic analysis. Irofulven plasma concentration–time profiles were best described by a two-compartment pharmacokinetic model. Clearance and central volume of distribution were not significantly influenced by individual characteristics, i.e. body weight (BW), body surface area (BSA), age and gender. Final parameter estimates of clearance and central volume of distribution were 616 l/h and 37 l, respectively, resulting in a very short terminal half-life of less than 10 min. A relatively high level of variability was observed in irofulven pharmacokinetics, which was mainly due to a significant residual variability, 39%. For a 30-min irofulven infusion, the optimal sampling schedule for clearance estimation using the Bayesian method was the three time points 0.35–0.45, 0.80 and 1–1.2 h from the beginning of a 30-min infusion. We conclude that after i.v. infusion of irofulven, plasma clearance was high and not dependent upon patient age, gender, BSA or BW.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Our objective was to identify a new active three-drug combination regimen consisting of paclitaxel (PTX), epirubicin (EPI) and cisplatin as first-line line chemotherapy for advanced ovarian carcinoma. A phase I study was carried out to evaluate the dose-limiting toxicity (DLT) and the maximally tolerated dose (MTD) of PXT and EPI in combination with a fixed dose of cisplatin every 4 weeks. Side-effects were recorded according to the NCI Common Toxicity Criteria. Patients were treated in cohorts of three with fixed-dose cisplatin 80 mg/m2and EPI 80→100 mg/m2and PXT 100→160 mg/m2until DLT was reached. Once MTD was identified, a single-step phase II study was therefore carried out to test the clinical activity and panel of toxicity of such regimen. Objective responses were recorded according to the WHO criteria. Time to progression and overall survival (OS) were secondary endpoints. The DLT was myelosuppression and, in more detail, febrile neutropenia, which occurred at the fifth dose level (PTX 140 mg/m2, EPI 100 mg/m2and cisplatin 80 mg/m2) in two out of three patients. Other side-effects were grade 3 mucositis in two out of three patients and grade 3 anemia in one case. The combination of cisplatin 80 mg/m2plus EPI 80 mg/m2and PCT 140 mg/m2every 4 weeks was considered as the MTD. In the phase II study a complete response was observed in six patients (33%) and a partial response in nine cases (50%) for an overall response rate of 83% [95% confidence limits (CL) 59–96%]. Median time to progression of patients with measurable disease was 16.4 months. Median OS was not reached after a follow-up of 42 months. This study demonstrated that PTX and EPI can be safely administered in combination with cisplatin to fit patients with advanced epithelial ovarian carcinoma. The three-drug regimen of cisplatin 80 mg/m2, EPI 80 mg/m2and PTX 140 mg/m2every 4 weeks is very active, at least in terms of objective response rate. This level of activity overlaps with the 95% CL of the activity of cisplatin alone; however, it does encourage future trials of the combination.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Our objective was to assess the distribution of paclitaxel in plasma and cerebrospinal fluid (CSF) in a cancer patient, and evaluate the role of the formulation vehicle Cremophor EL (CrEL) in drug distribution. Analysis of paclitaxel concentrations in CSF was performed using a triple-quadrupole mass spectrometric assay with electrospray ionization. Total and unbound paclitaxel levels in plasma were measured by liquid chromatography and equilibrium dialysis, respectively, and CrEL concentrations were determined by a colorimetric dye-binding microassay. Clinical samples were obtained from a 54-year-old female with breast cancer receiving a weekly regimen of paclitaxel (dose 60 mg/m2). The disposition of total paclitaxel in plasma was characterized by a bi-exponential elimination (terminal half-life 9.17 h) and a total clearance of 19.4 l/h/m2. The fraction of unbound paclitaxel in plasma ranged from 7.6 to 12.4% (unbound drug CL 176 l/h/m2). The plasma clearance of CrEL was 0.332 l/h/m2, whereas CrEL levels were undetectable in CSF (below 0.5μl/ml). Concentrations of paclitaxel in CSF (range 45.5–162 pg/ml) and unbound CSF:unbound plasma concentration ratios (range 0.093–9.53%) progressively increased up to 24 h, with a mean unbound drug fraction in CSF of 84±3.6% (range 81–88%). These findings indicate that there is substantial distribution of paclitaxel to CSF. Since the fraction of unbound paclitaxel is different between plasma and CSF, measurement of unbound paclitaxel is required to accurately assess the extent of drug penetration.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Advanced colorectal cancer (CRC) has a poor prognosis with a 5-year survival of only 5% despite treatment with chemotherapeutic agents. Response rate and overall survival varies little between the commonly used single agents, although combinations achieve better outcomes. It is well established that considerable heterogeneity exists between cancers of the same tissue type, but it has been difficult to establish this for CRC. We therefore investigated the heterogeneity of chemosensitivity in CRC using a modified version of theex vivoATP-tumor chemosensitivity assay (ATP-TCA) capable of handling infected tumor tissue. Fifty-three specimens of primary solid or malignant effusions of CRC were tested, of which 46 (87%) were evaluable. There were considerable differences in sensitivities between individuals. The most active single cytotoxic agents in the assay were identified as 5-fluorouracil, irinotecan and mitomycin C (MMC). Cells were exposed to combinations of drugs added simultaneously at the same concentrations tested as single agents. All drug combinations achieved greater growth inhibition than drugs used alone. MMC+gemcitabine was found to be the most effective combination in 83% of specimens. The ATP-TCA has previously been shown to be a good predictor of response to chemotherapy in other tissue types. The degree of heterogeneity demonstrated from these results suggests that the ATP-TCA could be used to identify patients who might benefit from specific chemotherapeutic agents alone or in combination.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that HOSM-1 cells, an osteosarcoma cell line established from human mandible, expressed mRNA for osteoblastic markers, such as alkaline phosphatase, osteonectin, osteocalcin and parathyroid hormone receptor, thus exhibiting an osteoblastic phenotype. We have investigated a possible role of cyclic nucleotide phosphodiesterases (PDEs) in osteosarcoma cells. RT-PCR analysis revealed that HOSM-1 cells expressed mRNA for PDE4A, 4B and 4C. In addition, rolipram, a specific inhibitor of PDE4, inhibited HOSM-1 cell proliferation. The finding that PDE4 is involved in proliferation of osteosarcoma cells suggests the possibility that PDE4 may be a new target for antitumor therapy.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Thisex vivostudy was designed to evaluate the effect of doxorubicin (Dox) on normal peripheral blood leukocytes (PBL) in terms of apoptosis and membranal expression levels of adhesion molecules. Blood was drawn immediately prior to and after Dox administration from 21 breast cancer patients, and incubated at room temperature for 24 h. Flow cytometry was employed in analysis of apoptosis with Annexin-V and protein membranal expression levels with monoclonal antibodies to CD49d, CD18, CD11a–c and CD63. Dox induced statistically significant apoptosis in all three major PBL subpopulations (p<0.01). Between 70 and 90% of samples underwent apoptosis in all PBL subgroups. No significant change was observed in the membranal level of CD63, CD49d and CD11a–c after chemotherapy in any PBL subpopulation. However, a significant reduction in the membranal level of CD18 was demonstrated in polymorphonuclear cells after Dox (p<0.005) both in apoptotic and non-apoptotic cells (p<0.05), suggesting a direct effect of Dox rather than an apoptosis-associated phenomenon. We observed the expected leukopenia 10 days after Dox administration with no correlation to apoptosis, suggesting that leukopenia by Dox is largely attributed to toxicity of blood progenitors.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID