摘要:

The tetracycline family includes tetracycline, doxycycline and minocycline, all of which have been used as antibiotics effectively for decades. New uses emerged for these compounds after their effect on mitochondrial function was discovered. Cytostatic and cytotoxic activity of these compounds was shown against cell lines of various tumor origins. In addition, tetracyclines and chemically modified tetracyclines inhibit the activity of several matrix metalloproteinases (MMPs). Given the importance of these enzymes in tumor cell invasion and metastatic ability, the potential use of tetracyclines in cancer therapy needed to be investigated. Col-3, a chemically modified tetracycline, is now the subject of clinical trials in cancer patients. However, the potential of tetracyclines in cancer therapy takes on an added dimension in the bone. MMPs have been shown to be important mediators of metastasis formation in the bone, contributing largely to the morbidity of breast cancer and prostate cancer patients. The natural osteotropism of tetracyclines would allow them to be highly effective in the inhibition of MMPs produced by osteoclasts or tumor cells in the bone. This hypothesis has now been confirmed by experimental evidence showing that doxycycline reduces tumor burden in a mouse model of breast cancer-derived osteolytic bone metastasis. This effect is likely due to a combination of multiple roles of doxycycline, including MMP inhibition and a negative effect on osteoclast differentiation and survival. These encouraging results have now paved the way for an ongoing trial of doxycycline in early combination therapy for breast cancer and prostate cancer patients.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

This prospective trial aimed to evaluate the therapeutic effects and systemic toxicities of capecitabine monotherapy and capecitabine treatment combined with biological response modifiers in patients with metastatic renal cell carcinoma. Fifty-four patients suffering from metastatic renal cell carcinoma progressing under first-, second- or third-line treatment entered the trial. Capecitabine was given orally at a dose of 2500 mg/m2daily divided into two doses for 14 days, followed by a 7-day rest in the monotherapy as well as in the combination treatment. This schedule was repeated in 3-week cycles. The combination therapy consisted of capecitabine and an immunotherapy treatment, which consisted either of interferon (IFN)-&ggr;1b (100 mg/day) administered consecutively 5 times weekly during weeks 1 and 2, and recombinant interleukin (IL)-2 (4.5 MU/day) administered on 4 consecutive days during weeks 3 and 4, every 6 weeks, or IFN-&agr; (6 MioIE/day) administered 3 times a week. Fifty-two patients are now evaluable for response and 54 patients for toxicity. We observed a partial response to treatment in five patients (9.6%), minor response in five patients (9.6%), stable disease in 32 patients (61.6%) and only 10 patients (19.2%) showed continued disease progression despite treatment. Outpatient capecitabine was well tolerated. We did not observe any WHO grade IV toxicities. We conclude that capecitabine monotherapy and capecitabine treatment in combination with biological response modifiers appear to be effective regimens with favorable toxicity profiles in patients with advanced renal cell carcinoma. Capecitabine monotherapy seems to be superior than the combination treatment because of its easier application form.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

We evaluated the effects of weekly short infusions of paclitaxel (PAC) on the development of a peripheral neuropathy (PNP) as primary endpoint. Patients with advanced cancer were randomized to a weekly regimen of PAC (100 mg/m2) infused over 1 versus 3 h. PNP was evaluated by a clinical score including sensory symptoms, strength, tendon reflexes and vibratory sense (range 0–12; PNP >3 points). Kaplan–Meier-type curves were calculated. In total, 22 study centers enrolled 121 patients, 92 assessable for analysis. The probability to exceed a PNP score of 3 increased from 0.20 versus 0.30 after six to 0.68 versus 0.47 after 12 administrations (1 versus 3 h:p = 0.66). After 12 weeks of therapy only a quarter of assessable patients were free of PNP. Cox analysis yielded a relative risk of 1.10 for 1-h infusions (p = 0.80). We observed a rapid increasing risk of PNP manifestation in the course of weekly PAC administrations without significant differences between 1- and 3-h infusions. This is in contrast to pharmacokinetic observations indicating that a shortening of infusion time might enhance neurotoxicity by increasing the AUC of Cremophor. A majority of patients experiencing neurotoxic effects require the investigation of potential nerve protectors in future clinical trials accompanying PAC therapy.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Liposomal daunorubicin replacing conventional anthracyclines may reduce toxicity and enhance efficacy of chemotherapy. In this phase I study, we evaluated liposomal daunorubicin (DaunoXome) in combination with vincristine and dexamethasone for toxicity, pharmacokinetics and potential efficacy in patients with multiple myeloma. The main objective was to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of liposomal daunorubicin combined with vincristine and dexamethasone (VLDD). Additionally, pharmacokinetics were determined at higher dose levels. Seventeen multiple myeloma patients were enrolled in this trial; 76% of the patients had relapsed or refractory multiple myeloma. Successive cohorts received liposomal daunorubicin at doses of 40, 60, 80 and 100 mg/m2on day 1 in combination with vincristine 1.4 mg/m2(day 1) and oral dexamethasone (40 mg, days 1–4). DLT occurred at 100 mg/m2. Liposomal daunorubicin at 80 mg/m2was well tolerated in this protocol and should be used for further phase II studies with the VLDD regimen. In this phase I trial, 64% of the patients achieved a partial remission or a minor response.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Combination chemotherapy with docetaxel (T), cisplatin (P), fluorouracil (5-FU) and leucovorin has been reported to have major activity against squamous cell carcinoma of the head and neck (SCCHN) administered as a 4-day (TPFL4) or 5-day (TPFL5) regimen. The purpose of this study was to evaluate the efficacy and toxicity of a modified TPFL regimen (m-TPFL) for locally advanced SCCHN, consisting of a modified dosage with docetaxel, cisplatin, 5-FU andl-leucovorin (l-LV) designed for Japanese patients. Organ preservation of the primary tumor site was also assessed. Thirty-four Japanese patients with locally advanced SCCHN were eligible. Docetaxel was administered as a 1-h i.v. infusion at 48 mg/m2on day 1; cisplatin, 24 mg/m2/day; 5-FU, 560 mg/m2/day andl-LV, 125 mg/body/day were delivered on days 1–4 by continuous i.v. infusion. This regimen was administered every 28 days. Patients who achieved a complete response (CR) after induction chemotherapy underwent radiation therapy alone. Ninety-one cycles were administered. The main hematological toxicity was neutropenia, classified as grade III or IV in 18.7% of cycles. The most common non-hematologic toxicities included anorexia, stomatitis and alopecia. The clinical overall response rate to m-TPFL was 88.2%, with 58.8% CRs and 29.4% partial responses. After definitive locoregional therapy, 25 of 34 patients were disease-free with preserved primary tumor site anatomy. Overall and progression-free survival rates at the 2-year follow-up are 92.8 and 75.3%, respectively. Our m-TPFL regimen designed for Japanese patients yielded excellent response rates with an acceptable toxicity profile in good-performance-status patients.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Either four or eight weekly rituximab infusions in relapsed or refractory low-grade or follicular B cell non-Hodgkin's lymphoma (NHL) are well tolerated and efficacious. This phase II trial investigated the safety and efficacy of six weekly rituximab doses in chemotherapeutically pre-treated relapsed or refractory low-grade NHL patients. Sixty-eight patients (median age 64 years) received six i.v. rituximab infusions 375 mg/m2weekly. All patients had received one or more prior therapies (median 2; range 1–18). Forty-two patients had progressive disease and were evaluated for toxicity and efficacy; 12 of these required re-treatment with six weekly rituximab infusions. Twenty-six patients received rituximab as remission consolidation therapy and were assessed for toxicity only. No patients discontinued because of adverse events. Most adverse events were National Cancer Institute grade 1 (2–9%) or 2 (3–5%) and usually occurred during the first infusion. No hematological abnormalities were observed. Overall response rate was 59% (median time to response 2 weeks) and 10 of 12 re-treated patients responded. Median time to progression for all patients was 14 months and for responders 21 months. More than half the 42 patients evaluated for efficacy and more than 70% of the 25 responding patients still survived longer than 3 years after treatment. The safety profile and efficacy achieved in this study compare favorably with those seen with four or eight weekly doses in pre-treated low-grade NHL.

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 of ultrafilterable oxaliplatin in metastatic cancer patients. Oxaliplatin was administered by 2- or 4-h infusions, 50, 65, 75, 85, 100 or 130 mg/m2to 56 patients. Blood samples were collected over 28 h. Plasma concentrations of ultrafilterable oxaliplatin were determined by flameless atomic absorption spectrophotometry. Population pharmacokinetic analysis was performed using a non-linear mixed-effects modeling method. Ultrafilterable oxaliplatin concentration–time profiles showed a secondary peak or a shoulder aspect post-infusion, attributed to the existence of an enterohepatic recirculation (EHR). They were best described by a two-compartment model incorporating an EHR component. Plasma clearance (CL) was related positively to body weight (BW) and negatively to serum creatinine (SCr), and was greater in male patients than in female patients. This covariate modeling resulted in a decrease in the interindividual variability for CL from 104 to 62%. The central distribution volume (V1) and inter-compartmental clearance (Q) were related to BW. Typical population estimates of CL, central distribution volume (V1), input rate constant into gallbladder (k1B) and lag time for drug reabsorption (TLAG) were 14.1 or 8.5 l/h (male or female patients), 24.9 l, 1.8 h−1and 2.0 h, respectively. The final pharmacokinetic model was validated using 200 bootstrap samples of the original data. We conclude that a two-compartment with EHR model adequately described ultrafilterable oxaliplatin pharmacokinetics, explaining a secondary transient increase in concentration. This study identified combined-covariate-effects ultrafilterable oxaliplatin clearance, supporting dose adjustment of oxaliplatin based on BW, gender and corrected for SCr level, if drug exposure is thought to be related to therapeutic or toxic issues.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

It has been reported that arsenic trioxide (As2O3) is an apoptosis inducer and radiation sensitizer for various cancer cell lines. In this study of breast cancer patients, we examined the combined effect of topical As2O3and radiation therapy on fungating and/or skin-infiltrating lesions of breast cancer. The dermatological, gastrointestinal, hematological, renal and hepatic toxicities of the treatment were also monitored. As2O3gel (0.05%) was applied to tumor lesions 1 h prior to delivery of each fraction, with the gel removed about 5 min before the irradiation. Superficial radiation was delivered using an electron beam from a linear accelerator. Every week, the tumor lesions were photographed to evaluate effectiveness, and blood was sampled to monitor changes in hemogram and biochemical profile. Seven breast cancer patients with cutaneous metastasis were enrolled in this study. In terms of tumor, the rates for complete, partial response and stable disease were 42.9 (three of seven), 42.9 (three of seven) and 14.3% (one of seven), respectively. The skin pain, assessed by a visual analog scale, and secretion from all of the seven superficial and fungating wounds decreased markedly after treatment. Significant bone marrow suppression or granulocytosis was not noted. Further, changes in renal and hepatic function were also not significant. It seems reasonable to conclude that As2O3may be an effective and safe radiosensitizer for palliative radiotherapy for skin-infiltrating lesions of breast cancer.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

We report one new case of hemolytic–uremic syndrome (HUS) and one case of digital necrosis after treatment with gemcitabine (Gemzar). Case 1, a 34-year-old man, was given first-line metastatic treatment with gemcitabine for a adenocarcinoma of the pancreas. After a cumulative dose of 10 000 mg/m2gemcitabine, the onset of subacute renal failure associated with hemolytic anemia of mechanical origin was observed. A diagnosis of probable gemcitabine-induced thrombotic microangiopathy was arrived at. Symptoms resolved after stopping the chemotherapy, in spite of the progression of the disease. Case 2, a 61-year-old man, was administered a combination of gemcitabine and a platinum salt as first-line metastatic treatment for carcinoma of the bladder urothelium. Following a cumulative dose of 10 000 mg/m2of gemcitabine, the patient suffered from bilateral peripheral vascular disease of somewhat acute onset with hemorrhagic lesions of the finger pads that became necrotic. The work-up was negative and a causal relationship was attributed to gemcitabine. The patient made good progress when given an i.v. infusion of Ilomedine (iloprost trometamol) and chemotherapy was withdrawn. We conclude that gemcitabine must be added to the list of drugs that cause HUS and necrotizing vasculitis.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The way a tumor cell dies is believed to influence both its engulfment by dendritic cells (DC) and access of the relevant antigen(s) to the cross-presentation pathway. Here we have studied the effect of lymphokine activated killer (LAK) cells, &ggr;-radiation and the antimetabolite drug 5-fluorouracil (5-FU) on tumor uptake by HLA-matched DC, and DC presentation of tumor antigens to autologous T lymphocytes. LAK cells and radiation were the best inducers of apoptotic death (Annexin-V+/propidium iodide−) on the gastric cell line KATO III and a primary gastric carcinoma, respectively. The highest rate of tumor uptake by monocyte-derived, granulocyte macrophage colony stimulating factor/interleukin (IL)-4-driven DC was associated with 5-FU, followed by radiation. These treatments also induced high levels of heat shock protein (hsp70). In contrast, only DC that had been taken up 5-FU- or LAK-treated tumors up-modulated IL-12 and presented tumor-associated antigens with increased efficiency, as shown by class I MHC-restricted interferon-&ggr; release and cytotoxic responses by autologous lymphocytes. Together, these data indicate that apoptotic death induced by anti-cancer therapies can induce distinct patterns of class I MHC cross-presentation of gastric carcinoma-associated antigens to cytotoxic T lymphocyte precursors.

ISSN:0959-4973    

出版商:OVID    

年代:2003

数据来源: OVID