ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Targeting the A3 adenosine receptor (A3AR) by adenosine or a synthetic agonist to this receptor (IB-MECA and Cl-IB-MECA) results in a differential effect on tumor and on normal cells. Both the adenosine and the agonists inhibit the growth of various tumor cell types such as melanoma, colon or prostate carcinoma and lymphoma. This effect is specific and is exerted on tumor cells only. Moreover, exposure of peripheral blood mononuclear cells to adenosine or the agonists leads to the induction of granulocyte colony stimulating factor (G-CSF) production. When given orally to mice, the agonists suppress the growth of melanoma, colon and prostate carcinoma in these animals, while inducing a myeloprotective effect via the induction of G-CSF production. The de-regulation of the Wnt signaling pathway was found to be involved in the anticancer effect. Receptor activation induces inhibition of adenylyl cyclase with a subsequent decrease in the level of protein kinase A and protein kinase B/Akt leading to activation of glycogen synthase kinase-3&bgr;, a key element in the Wnt pathway. The oral bioavailability of the synthetic A3AR agonists, and their induced systemic anticancer and myeloprotective effect, renders them potentially useful in three different modes of treatment: as a stand-alone anticancer treatment, in combination with chemotherapy to enhance its therapeutic index and myelprotection. It is evident that use of the A3AR agonist for increasing the therapeutic index of chemotherapy may also invariably give rise to myeloprotection and vice versa. The A3AR agonists are thus a promising new class of agents for caner therapy.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Originally isolated from an Australian plant, acronycine is an antitumor alkaloid with poor water solubility and low potency. The modest antitumor activity of this compound was markedly improved by the total synthesis of original analogs resulting in the selection of S23906-1, a diester derivative of 1,2-dihydrobenzo[b]acronycine. S23906-1 is characterizedin vitroby a high potency in clonogenic assays and uncommon cell cycle pertubations.In vivo, this compound demonstrated a selectivity for human solid tumors as compared to murine transplantable tumors. The unique pharmacological profile of S23906-1 was particularly defined by a broad antitumor efficacy when administered i.v. or orally on aggressive orthotopic models of human lung, ovarian and colon models with comparable or better activity than clinically used anticancer drugs. The molecular mechanism of action of S23906-1 could involve DNA alkylation, modulation of cyclin E protein levels and inhibition of DNA synthesis leading to apoptosis. Ongoing preclinical toxicological studies will help to define the potential of this novel agent which is already considered as a valuable candidate for clinical studies.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Standard chemotherapy for advanced gastric cancer remains undefined. Two of the most popular regimens—ECF [epirubicin–cisplatin–5-fluorouracil (5-FU)] and PELF (cisplatin–epirubicin–5-FU–leucovorin)—have been shown to be active, but each has limitations. Phase II trials show that single-agent docetaxel is an active agent in advanced gastric cancer, producing overall response rates (ORRs) of 17.5–24%. Docetaxel has also been shown to lack cross-resistance with other drugs in gastric cancer, and is likely to be at least additive to cisplatin and 5-FU. Phase II results of docetaxel combinations in advanced gastric cancer are encouraging. Docetaxel–cisplatin has yielded response rates similar to those achieved by ECF and PELF. Adding 5-FU to docetaxel–cisplatin has achieved an ORR of 52 versus 45% for docetaxel–cisplatin in a randomized phase II trial. Docetaxel-based regimens demonstrate acceptable tolerability despite predictable hematotoxicity. Neutropenia, the major toxicity, is manageable by dose modification or by using prophylactic granulocyte colony stimulating factor. Several phase III trials are now ongoing, including a large-scale trial of docetaxel–cisplatin–5-FU versus cisplatin–5-FU. Results will show whether docetaxel improves overall response and survival, as suggested in the phase II setting.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The goal of the present paper is to review how treatment of advanced colorectal cancer has evolved during the last 10 years and to make some suggestions on how that disease could be managed today. 5-Fluorouracil (5-FU) combined with folinic acid (FA) remains the basis for advanced colorectal cancer treatment. In Europe, infusional 5-FU is considered to be more active and better tolerated than bolus 5-FU. New agents including oral 5-FU prodrugs UFT/FA, and capecitabine, tomudex, irinotecan and oxaliplatin have been shown active in advanced colorectal cancer. At presentation the combination of infusional 5-FU/FA with irinotecan or oxaliplatin is considered to be superior to any of these agents used alone, yielding a median survival of up to 16–19 months. Second-line therapy could further prolong survival in selected patient populations. Eventually chemotherapy could allow curative resection of previously unresectable hepatic and pulmonary metastases.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The aim of this study was to characterize the population pharmacokinetic of vinorelbine in elderly patients and to propose a limited-sampling strategy to estimate individual pharmacokinetic parameters. Vinorelbine was administered by a 10-min continuous infusion at a dose of 20–30 mg/m2. The population parameters were computed, using a three-compartment model, from an initial group of 27 patients. Twelve additional courses were used for model validation and evaluation of eight different limited-sampling strategies. The inter-individual variability of CL was explained by a linear dependency with age. The population average parameters and the interindividual variabilities (CV%) were: CL=47.1 l/h (31.7%),V=16.6 l (64%),k21=0.776 h−1(20%),k31=0.0346 h−1(15.2%),&agr;=0.431 h−1(6.84%) and&bgr;=0.0167 h−1(25%). Bayesian estimation with three measured levels (end of infusion, and 6 and 48 h) can be selected, because it allows adequate estimation of CL, elimination half-life and vinorelbine concentrations with a non-significant bias. Moreover, the choice of these three sampling times presents practicality advantages for the patient's comfort. Vinorelbine clearance decreasing with age and AUC being a good predictor of several toxicity end points during vinorelbine treatment, the limited-sampling strategy developed in this paper may be clinically relevant.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

We characterized the toxicity and determined the maximum tolerated dose of non-break weekly paclitaxel (Taxol) in chemotherapy-naive cancer patients, and studied pharmacokinetics of the formulation vehicle Cremophor-EL with this schedule. Twenty-three patients with primary refractory solid tumors received weekly paclitaxel at the dose range of 70–200 mg/m2. As dose-limiting toxicity we defined granulocytopenia grade ≥2 causing a treatment delay for more than 2 weeks, or febrile neutropenia or grade >2 organ-specific toxicity. Plasma kinetics of Cremophor-EL were analyzed over the first five courses of treatment. Non-break weekly paclitaxel was feasible at doses up to 110 mg/m2, while granulocytopenia precluded scheduled administration of doses ≥130 mg/m2. Clinically relevant peripheral neurotoxicity tended to occur at around 1500 mg/m2cumulative dosage at weekly doses ≥110 mg/m2. Detectable Cremophor-EL levels were found in all pre-dose samples, but there was no evidence of accumulation up to the sixth course. Our results, discussed in the light of an overview of published data, suggest that chronic weekly administration of paclitaxel is feasible and with a lack of significant accumulation of Cremophor-EL levels at doses up to 90 mg/m2.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

A phase II study was performed to assess the safety and efficacy of mitoxantrone and cisplatin in locally recurrent and/or metastatic carcinomas of the salivary glands. Between May 1997 and March 2001, a total of 14 patients were entered on this trial. All of them had previously undergone radical resection and 10 were subsequently treated with adjuvant radiation therapy with (n=3) or without (n=7) concomitant chemotherapy. Therapy according to the study protocol consisted of mitoxantrone given as i.v. bolus on day 1 at a dose of 12 mg/m2and cisplatin given as 90-min infusion at a dose of 30 mg/m2on days 1–3. We observed two partial responses (14.3%) and stabilization of disease in nine patients (64.3%); progression during therapy was noted in only three cases (21.4%). The median time to progression was 15 months (range 2–36) and the median survival time was 27 months (range 4–54). Myelosuppression was commonly observed. Leukocytopenia occurred in all patients, and was grade 3 or 4 in three (21%) and four (29%) patients. WHO grade 3 thrombocytopenia and anemia was seen in three (21%) and four (29%) patients, respectively. Non-hematologic toxicity was in general mild to moderate except for two cases (14%) of grade 3 nausea and vomiting; overall incidence rates were nausea and vomiting (n=14), stomatitis (n=6), diarrhea (n=3), alopecia (n=11), infection (n=7), increase of serum creatinine (n=3), and peripheral neuropathy (n=3). The combination of mitoxantrone and cisplatin seems to be an active and fairly well-tolerated regimen for the treatment of advanced salivary gland cancers. According to the observed high rate of abrogating progressive disease for a long duration, and the resulting promising progression-free and overall survival time, further investigation seems warranted.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The aim of this study was to evaluate the toxicity and efficacy of combination chemotherapy with weekly 24-h continuous infusion of 5-fluorouracil (5-FU)/folinic acid, weekly paclitaxel and 3-weekly cisplatin in patients with unresectable, locally advanced or metastatic gastric adenocarcinoma. Between November 1999 and November 2001, 29 chemotherapy-naive patients (13 male and 16 female) with a median age of 56 years (range 22–72) were consecutively enrolled at three centers. 5-FU 2 g/m2was given weekly over 24 h i.v. preceded by folinic acid 500 mg/m2as a 2-h infusion. Paclitaxel 80 mg/m2was administered as a 1-h infusion weekly and cisplatin 50 mg/m2as 1-h infusion on days 8 and 29. Six weeks of therapy (days 1, 8, 15, 22, 29 and 36) followed by 1 week of rest was considered one cycle. A median of 3 cycles (range 1–5) was administered to 29 patients with a total of 73 cycles applied. All patients were assessable for toxicity and survival, 28 patients were assessable for response (one patient received less than one complete cycle and could not be evaluated for response). Four patients (14%) obtained a complete response and 10 patients (34%) a partial response (overall response rate 48%, 95% CI 29–68%). Seven patients (24%) had stable disease. Seven patients (24%) had progressive disease during or within 4 weeks after treatment. The median progression-free and overall survival times were 8 months (range 1–23) and 11 months (range 1–23), respectively. Overall toxicity was acceptable. Hematological toxicity was favorable with only one patient (3%) experiencing WHO grade 3/4 leukocytopenia and one patient (3%) WHO grade 3/4 anemia. Non-hematologic WHO grade 3/4 toxicities included alopecia in 19 (66%), nausea/vomiting in six (21%), diarrhea in six (21%), neurotoxicity grade 3 in three (10%) and infection in three (10%) patients. A total of 42 applications (10%) (range 0–5) had to be postponed and dose reductions of at least one drug was necessary in 37% of applications. In three patients (10%) treatment was stopped because of toxicity. All patients were treated on an outpatient basis. Thus, the combination of weekly paclitaxel, cisplatin and continuously infused 5-FU/folinic acid appears to be a highly active regimen for the treatment of patients with advanced gastric cancer. Compared with our previous experience with the same combination of drugs but using paclitaxel at 175 mg/m2given every 3 weeks, the protocol with weekly application of paclitaxel 80 mg/m2shows a reduced incidence of hematologic toxicity, particularly leukopenia. Other organ toxicities apart from a slightly higher incidence of peripheral neuropathy were comparable between the two treatment protocols. Efficacy with a response rate of 50% was well preserved by this weekly regimen.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

A phase I study was conducted to determine dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of carboplatin combined with irinotecan and docetaxel on a divided schedule with recombinant human granulocyte colony stimulating factor (rhG-CSF) support in patients with stage IIIB or IV non-small cell lung cancer. Carboplatin was given at the dose of AUC5 on day 1. Irinotecan and docetaxel on days 1 and 8 were administered at a starting dose of 40 and 30 mg/m2as level 1. Subsequent levels were: irinotecan/docetaxel (in mg/m2), 50/30 (level 2), 60/30 (level 3) and 60/35 (level 4). rhG-CSF was given at 50 mg/m2on days 5–15. Cycles were repeated every 3 weeks. Between May 1999 and April 2001, 31 patients were registered in this phase I study. Level 4 was judged as the MTD. The DLTs were considered diarrhea and febrile neutropenia. The overall response rate was 32.3% and median survival was 490 days with 1-year survival of 65.1%. We conclude that both irinotecan 60 mg/m2and docetaxel 30 mg/m2on days 1 and 8 in combination with an AUC5 of carboplatin on day 1 with rhG-CSF support is recommended for phase II study. The response rate and survival data in this phase I study are encouraging. We considered that the pathogenesis of diarrhea involved not only direct cytotoxic damage to the mucosa, but also bacterial overgrowth.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID