摘要:

Prostate cancer is the most prevalent cancer amongst males and accounts for 13% of cancer deaths in this population in the US. Aggressive, androgen-independent, metastatic prostate cancer is incurable, and the search for new therapies has been directed towards identifying agents that block proliferation and induce differentiation and/or apoptosis of prostate cancer cells. Retinoid receptor agonists, such as all-transretinoic acid, can induce apoptosis of prostate cancer cells, but clinical studies have demonstrated only mild to moderate efficacy. Retinoic acid receptor antagonists are a new class of retinoids, and pre-clinical studies have shown that they potently inhibit the growth of prostate cancer cells and induce apoptosis. Here, we review whether retinoids have a role in the fight against prostate cancer.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Neo-adjuvant, dose-dense docetaxel, 100 mg/m2every 2 weeks ×4 cycles, was administered to 12 patients with locally advance breast cancer (LABC) (10 stage IIIa and three stage IIIb). Eligibility requirements included a PS 0–2, normal hepatic and renal function, and radiologic absence of metastatic disease. Filgrastim [granulocyte colony stimulating factor (G-CSF)] was started 1 day after chemotherapy and was given for 6 days. Complete blood counts were determined weekly. Surgery was planned upon recovery from the last dose of docetaxel and followed by 4 cycles of adjuvant doxorubicin plus cyclophosphamide (AC) and radiotherapy. Patients with ER+status received tamoxifen. The median age was 45 (range 34–73) and pre-treatment pathology revealed poorly differentiated infiltrating duct carcinoma in 11 and infiltrating lobular cancer in one, with positive ER/PR status in five. Twelve patients were treated, and all are evaluable for response and toxicity. Nine patients had a major clinical tumor response with five PR and four pathologic complete responses (pCR rate of 33%). Three patients (of whom two with stage IIIb) had progressive disease and went on to receive neo-adjuvant therapy with AC. There was one instance of grade 3 hematologic toxicity (neutropenic fever in one G-CSF non-compliant patient). There were two instances of grade 3 extra-hematologic toxicity: one patient had severe pain and one had treatment-related fatigue. After a median follow-up of 20 months (range 7–49 months) all patients are alive and eight of nine responders remain progression-free. Despite the small size of our study, we believe that dose-dense neo-adjuvant docetaxel is well tolerated and its activity warrants confirmation in a larger number of patients.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

In vivoantitumoral activity, pharmacokinetics (PK) and biodistribution of a new liposomal formulation of vincristine (VCR-Lip) were compared to VCR in aqueous solution (VCR-Conv). VCR was entrapped into a vesicular phospholipid gel (VPG) consisting of densely packed liposomes. Redispersed VCR-containing VPG (VCR-Lip) consisted of 54% liposomally entrapped and 46% free VCR.In vivoefficacy of VCR-Lip versus VCR-Conv was tested using the s.c. growing human small cell lung carcinoma LXFS 650 and the human mammary carcinoma MX1. PK and biodistribution were evaluated using radiolabeled drug and lipid in LXFS 650 tumor-bearing mice. VCR-Lip at a dose of 1.0 mg/kg (dose near the maximum tolerated dose) led to partial remissions in the MX1 tumor xenograft model (T/C=3.9%). VCR-Conv at an equitoxic dose of 0.6 mg/kg produced only a tumor growth inhibition (T/C=7.0%). In LXFS 650 tumor-bearing mice, VCR-Lip was highly active at doses of 0.75 (T/C=0.7%) and 1.0 (T/C=0.0%) mg/kg, and complete tumor regressions were observed. In contrast, equitoxic doses of VCR-Conv (0.6 mg/kg) resulted only in less pronounced tumor remissions (T/C=4.1%). The PK study revealed that VCR-Lip achieved an over 10-fold higher plasma AUC (22.6 μg·h/ml) than VCR-Conv (2.16 μg·h/ml). Moreover, tumor drug levels were 2.3-fold higher when VCR was injected as VCR-Lip in comparison to VCR-Conv. In some cases, however, VCR-Lip as well as blank VPG appeared to be toxic. We conclude that VCR-Lip is an effective VCR delivery system with superior antitumor activity compared to VCR-Conv. The enhancedin vivoefficacy can be explained by sustained release and passive tumor targeting.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

E7070 is a novel sulfonamide anticancer agent that arrests the G1/S phase of the cell cycle. Preclinical and phase I studies have demonstrated non-linear pharmacokinetics of the drug. The objective of this study was to quantify the excretion of E7070 and the metabolite 1,4-benzene-sulfonamide (M1) in cancer patients. E7070 (1000 mg) radiolabeled by14C in the benzene disulfonamide moiety (cohort 1,n=6) or in the indole moiety (cohort 2,n=7) was i.v. infused over 1 h. The levels of radioactivity in plasma, red blood cells, urine and feces were determined by liquid scintillation counting, and the E7070 and M1 concentrations in plasma, urine and feces were determined by coupled liquid chromatography–tandem mass spectrometry (LC/ESI-MS/MS). In plasma, the mean area under the concentration–time curve (AUC) based on radio-activity measurements (32.5 and 28.9 h · mM in cohorts 1 and 2, respectively) was substantially higher than the mean AUC of E7070 (3.8 h · mmol/l) and M1 (0.1 h · mmol/l) in all patients. The excretion of radioactivity (mean±SD) as a percentage of administered radioactivity was higher in urine [63.7±9.8% (cohort 1) and 61.5±5.5% (cohort 2)] than in feces [22.7±2.6% (1) and 21.1±3.1% (2)] during a mean collection period of 11 days. In both cohorts, the contribution of urinary and fecal recovery of E7070 (2.3 and 2.7%, respectively) and M1 (5.3 and 5.1%, respectively) was low. Subsequent HPLC analysis with online radioisotope detection of urine showed that the high radioactivity levels are caused by compounds other than E7070 and M1. The major metabolite is formed by glucuronidation of a hydroxylated metabolite of E7070. In conclusion, the excretion of the benzene sulfonamide and the indole moieties of E7070 was the same with a higher renal than gastrointestinal excretion. E7070 is extensively converted into currently unidentified metabolites. Glucuronidation is a major metabolic pathway.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

We conducted a phase I/II trial to determine the maximum tolerated dose (MTD) and the efficacy of prolonged infusion of cisplatin and oral etoposide in the treatment of advanced non-small cell lung cancer (NSCLC). Cisplatin was given via an infuser in escalating doses of 5, 6.5, 8, 9 and 10 mg/m2/day for 14 days along with etoposide at a fixed dose of 50 mg/m2/day orally followed by a 2-week rest period. All patients had stage IIIB or IV NSCLC. A cisplatin dose of 8 mg/m2/day was determined as the MTD. In the 13 patients treated at this dose level, grade III and IV toxicities were mainly hematologic including neutropenia (n=5), febrile neutropenia (n=4), thrombocytopenia (n=3) and anemia (n=6). Grade III/IV renal toxicity occurred in one patient. There were no treatment-related deaths. One patient had a partial response and three patients had stable disease. Thus, although the described regimen of cisplatin/etoposide is reasonably well tolerated, it does not appear to be better than the same combination administered over a shorter duration, in spite of a cumulative dose of 112 mg/ m2of cisplatin and 700 mg/ m2of etoposide per cycle.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

We sought to define the tolerance of 9-amino-20(S)-camptothecin (9-AC) when given by the i.p. route to patients with cancer in the peritoneal cavity consisting of nodules that did not exceed 1 cm in maximum diameter. 9-AC was given in six fractions over 12 days, at doses ranging from 1.25 to 13.5 mg/m2in cycles repeated every 28 days. Dose escalations after the first two dose levels took place in cohorts of three patients, with expansion of the dose level once a dose-limiting toxicity (DLT) was encountered. All patients had blood and i.p. pharmacokinetic (PK) analysis during cycle 1 of each dose level. Topoisomerase (Topo) I signal was serially measured in peripheral blood mononuclear cells (PBMCs) in blood and cells collected in i.p. cytologic washings. Twelve patients received 31 cycles of 9-AC. Tolerance to repeated i.p. drug administration was generally excellent. The DLT was neutropenia encountered at the highest dose level in two patients, whereas the dose of 9 mg/m2was well tolerated. The DLTs were associated with peak plasma levels ranging from 47 to 81 ng/ml and also depletion of Topo I in PBMCs. The i.p.:plasma AUC ratio (±SD) was 11.5 (±3.8). Two patients had objective evidence of clinical benefit and only one of seven patients deemed evaluable for response had progressive disease. We conclude that i.p. 9-AC demonstrates excellent local tolerance at a dose and schedule associated with evidence of systemic effects. A dose of 9 mg/m2/cycle administered in a schedule of six divided fractions is suitable for further evaluation against tumors involving primarily the peritoneal cavity.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Doxetaxel (DCT) and mitoxantrone (MX) are highly active and potentially synergistic agents in the treatment of metastatic breast cancer (MBC). This pilot study evaluates the combination of dose-dense DCT and MX in patients with MBC to determine the efficacy and toxicity of this therapy. Thirty-six patients (56.1±1.7 years) were studied. The patients received DCT (35 mg/m2q1w) and MX (6 mg/m2 q2w) for 6 weeks of an 8-week interval. Patients with tumor response or stable disease (SD) continued the treatment for a maximum of two additional periods. Hematologic and non-hematologic parameters were determined using the WHO common toxicity score. During this study 14 patients (40%) experienced partial response, 14 (40%) SD. In 20% of the cases the disease progressed on therapy. The treatment with DCT and MX was well tolerated. Seventeen patients (47%) experienced grade 3 leukopenia. Other hematologic and non-hematologic side effects did not exceed grade 2. One patient died during therapy because of a pulmonary embolism, which was unlikely related to active agents. Dose-dense DCT and MX combines both clinical activity and convenience for the patient. Therefore, we conclude that this regimen is a promising therapy in MBC, which warrants confirmation by large-scale clinical trials.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The prognosis for advanced esophageal carcinoma is poor with a median survival of 9–12 months and 5-year-survival rate of 10–20%. Combination chemotherapy with cisplatin and 5-fluorouracil (5-FU) is considered to be the standard therapy, but has a high potential of side effects and is usually not given on an ambulatory basis. This phase I study was designed to find the maximum tolerated dose (MTD) of weekly cisplatin in combination with standard doses of gemcitabine (1000 mg/m2, 30 min) and 5-FU (750 mg/m2, 24 h)/folinic acid (200 mg/m2, 30 min). All drugs were to be given on a day 1, 8, 15 and 22 of a 6-weekly cycle in an outpatient setting. Nineteen chemonaive patients with inoperable stage IIa, III and IV squamous cell carcinoma and adenocarcinoma of the esophagus were enrolled into the study. Eight, six and five patients were enrolled at cisplatin dose levels 0 (20 mg/m2), I (25 mg/m2) and II (30 mg/m2), respectively. One hundred and eighty-one out of 187 treatments (55 cycles) were given on an outpatient basis. The dose-limiting toxicities of this schedule were leukopenia and thrombocytopenia. Other side effects were mild. Dose level II (30 mg/m2) was defined as the MTD for cisplatin when used in this combination and schedule. Partial responses were observed in 10 of the 19 enrolled patients. The side effect profile seen in this study in combination with the preliminary evidence of efficacy justifies further testing in a phase II setting with a cisplatin dose of 25 mg/m2and offers a treatment option for patients in an outpatient setting.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

This phase II study evaluated the activity of gemcitabine (Gemzar) plus cisplatin (Platinol) as first-line treatment of advanced epithelial ovarian cancer. Forty-two chemonaive patients with advanced (stage III and IV) epithelial ovarian cancer received gemcitabine 1250 mg/m2on days 1 and 8 and cisplatin 100 mg/m2on day 1, every 3 weeks, up to eight cycles. The median number of cycles completed was 5 (range 2–8). Of the 41 patients evaluable for tumor response, 20 had a partial response and nine had a complete response, for an overall clinical and pathologic response rate of 70.7% (95% CI 56.8–84.6%). Median overall survival for all 42 patients was 23.4 months (95% CI 15.9–29.9 months) and the median progression-free survival time was 10.4 months (95% CI 9.4–13.5 months). The combination was generally manageable. Hematologic toxicity (grade 3/4 neutropenia: 31.0/21.4%; grade 3/4 thrombocytopenia: 9.5/4.8%; grade 3/4 anemia: 11.9/0%) and nausea and vomiting (grade 3/4: 35.7/31.0%) were the most common toxicities. There was one toxic death (septic shock due to hematologic toxicity-induced infection). We conclude that gemcitabine plus cisplatin is active and feasible as first-line treatment of advanced epithelial ovarian cancer. Further clinical trials with the addition of gemcitabine to first-line treatment appear warranted.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Hepatic and peritoneal metastases are the most frequent metastatic lesions in patients with gastrointestinal stromal tumors (GIST), and may result in intra- or extrahepatic cholestasis and altered drug metabolism. While the tyrosine kinase inhibitor imatinib, which has been recently shown to represent the treatment of choice for GIST, is primarily metabolized by the liver, data on the pharmacokinetics and the tolerability of imatinib in patients with increased cholestasis parameters are not yet available. We here report on two patients who received imatinib in the presence of increased bilirubin and/or cholestasis parameters. With a follow-up duration of 3–4 months, we observed no toxicities outside of well-known side effects including some degree of myelosuppression and fluid retention. This report may aid in the decision of imatinib being given under close surveillance to this kind of patients.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID