摘要:

Four newly synthesized antitumor steroidal compounds were compared, on a molar basis, regarding their ability to induce sister chromatid exchanges (SCEs) and cell division delays. The concept of designing and developing these compounds (1–4) is to enhance the anticancer activity of esteric steroidal derivatives of nitrogen mustard by introduction of a keto group at the 7-position of the D5steroidal skeleton, and a double bond between positions 6 and 7 of the B ring of the steroidal nucleus. In our study, the cytogenetic and antileukemic effects of these newly synthesized compounds are reported. The four substances induced statistically significant enhancement of SCEs and of cell division delays, and in both schedules used, therapeutic effects. However, compounds 1 and 3 showed increased genotoxicity towards human lymphocytes (p<0.001) and antileukemic activity towards P388 leukemias (p<0.001), compared to compounds 2 and 4. It seems that the introduction of a keto group at the 7-position of the steroidal skeleton enhances the antitumor effect of these substances in comparison with our previous studies with the corresponding compounds characterized by the absence of the 7-keto group. Therefore, thein vivoantitumor effect of the four compounds appears to correlate well with thein vitrocytogenetic effect caused by these chemicals.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ZD9331 is a potent thymidylate synthase inhibitor. Renal and hepatic clearances were found to be important routes of elimination. The objectives of this pharmacologic trial were to investigate the effect of renal impairment on the pharmacokinetics of ZD9331, to study the toxicity profile and to document any antitumor effects of ZD9331 when administered i.v. to patients with different degrees of renal impairment. Patients were treated with ZD9331 130 mg/m2given as an i.v. infusion on day 1 of a 4-week cycle to allow full pharmacokinetic assessment. Subsequent cycles involved the administration of ZD9331 on days 1 and 8, every 3 weeks. Patients were stratified according to their renal function assessed by the creatinine clearance: normal renal function (creatinine clearance ≥60 ml/min), mildly impaired renal function (creatinine clearance ≥40 to <60 ml/min) and moderately impaired renal function (creatinine clearance >25 to <40 ml/min). For pharmacokinetic analysis plasma sampling was performed during the first course and assayed using a validated liquid chromatographic tandem mass spectrometry assay. Twenty-three patients were entered on the study, of whom 21 received 130 mg/m2ZD9331 in the first treatment cycle. No relationship was seen between renal impairment and plasma clearance nor with the area under the concentration–time curve of free ZD9331. Increasing renal impairment was associated with a greater incidence of myelosuppression. No predictive relationship between the clearance of free ZD9331 and the degree of renal impairment as determined by creatinine clearance could be assessed. However, data from this trial indicate that increased renal impairment may be associated with greater ZD9331-induced toxicity, particularly myelosuppression, although this cannot be attributed to any alteration in the plasma pharmacokinetics of ZD9331. Therefore, it may be necessary to administer a reduced dose of ZD9331 to patients with impaired renal function.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

The efficacy and safety of docetaxel–epirubicin chemotherapy in the treatment of metastatic breast cancer was investigated in Chinese women. Three-weekly cycles comprised epirubicin 75 mg/m2i.v. followed 1 h later by docetaxel 75 mg/m2i.v. After 3 cycles, responding patients received a further 3 cycles, followed by 3 cycles of docetaxel alone. Forty-six patients entered the study, of whom 37% had received prior adjuvant chemotherapy. Three patients withdrew due to toxicity and were not evaluable for response. There were five complete responses and 31 partial responses, giving an overall response rate of 83.7% (95% CI 72.7–94.8%). The median time to progression was 10.96 months (95% CI 7.76–12.86) and median survival was 24.2 months (95% CI 16.6–). The most common grade 3/4 adverse events were neutropenia (96% of patients) and neutropenia with fever (39%). Hepatotoxicity occurred in six patients, two being attributable to hepatitis B virus reactivation. No patients suffered grade 3/4 cardiac toxicity and there were no treatment-related mortalities. Quality of life aspects deteriorated after 3 cycles, but there was a trend towards improved emotional aspects after 9 cycles. We conclude that docetaxel–epirubicin chemotherapy is highly effective for recurrent metastatic/locoregional breast cancer, with myelosuppression being the main toxicity.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

In clinical practice, regional chemotherapy of the liver applied as ‘hepatic arterial infusion’ (HAI) is often limited by device dysfunction or hepatic arterial obstruction. We report the case of a patient with mixed hepato/cholangiocellular carcinoma in which HAI with folinic acid (FA) and 5-fluorouracil (5-FU) was continued after thrombotic occlusion of the A. hepatica, resulting in a flow of drugs into the V. portae (via A. lienalis and V. lienalis). By using this ‘spleno-portal’ access for further chemotherapy with FA/5-FU, long-term control of the patient's disease was achieved. Analyzing our experience with this and three other patients with hepatic arterial thrombosis in which we continued HAI, a total of 33 regional treatment courses were applied, containing 5-FU/FA, mitomycin C, doxorubicin or combinations of these drugs. No unexpected toxicities were observed. In addition, the clinical course of three of those four patients strongly suggests the effectiveness of this approach. Thus, our results indicate that thrombosis of the A. hepatica does not necessarily have to result in an interruption of HAI. Continuation of regional chemotherapy despite hepatic arterial occlusion preserved control of intrahepatic tumor manifestations in patients who previously responded to regular HAI.

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:0959-4973    

出版商:OVID    

年代:2002

数据来源: OVID