摘要:

Doxorubicin and paclitaxel both display strong antitumor activity in the treatment of breast cancer. The optimal schedule of this combination, however, remains undefined. In this phase I and pharmacologic study, we administered weekly 12 mg/m2doxorubicin as a bolus infusion immediately followed by a 1 h 80 mg/m2 paclitaxel infusion to patients with metastatic breast cancer. A total of 119 weekly courses were delivered to seven patients. Grade IV neutropenia was observed in two patients at the first dose level, thus already defining the maximum tolerated dose. Pronounced non-hematologic toxicities were mild neuropathy (grade I: 39%) and stomatitis (grade I:19%, grade II: 8%). No signs of cardiac toxicity were observed with this dose schedule. Three partial responses were achieved in this group of heavily pretreated patients. The pharmacokinetics of paclitaxel, doxorubicin and Cremophor EL with this schedule were analyzed. Overall, the schedule was well tolerated and combined with its preliminary response rate justifies further evaluation in phase II studies.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Exemestane is an Irreversible, steroidal, oral aromatase inhibitor under evaluation in postmenopausal women with advanced breast cancer. A phase I study was conducted in 27 postmenopausal patients who were candidates for hormone therapy because they had advanced breast cancer and estrogen receptor-positive or unknown status. Most patients were moderately or heavily pretreated. Cohorts of at least three patients received sequentially escalating daily oral doses of 5–600 mg. The median duration of exemestane treatment was 13 weeks (range: 3–166 weeks). The maximal tolerated dose was not reached because of lack of treatment related grade 3 or 4 toxicity. The most common adverse events, including those not related to treatment, were mild to moderate headache (44% of patients), dizziness (33%), nausea (33%), hot flushes (30%) and tumor-related pain (30%). There were three complete and four partial responses for an objective response rate of 26% (95% CI: 11.1–46.3%) in the intent-to-treat population; the median duration of response was 74 weeks (95% CI: 48–99 weeks). Exemestane, at the dose of 25 mg, maximally suppressed estradiol, estrone and estrone sulfate serum levels to 13, 5 and 10% of baseline, respectively. Exemestane appears to suppress estrogen, be well tolerated and have antitumor activity in postmenopausal women with advanced breast cancer. A large, safe therapeutic window of up to 600 mg was defined. In view of its safety and estrogen-suppression profiles, the most favorable effects were observed at the 25 mg daily dose.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Our aim was to investigate the pharmacoklnetic behavior of 5-fluorouracil (5-FU) in pancreatic fluid and to evaluate its penetration characteristics in post-pancreatoduodenectomy patients. After completing the external drainage of the pancreatic duct during pancreatoduodenectomy surgery, eight patients were administered 1.0 g 5-FU i.v. by a 5 min infusion after the eighth day post-surgery on average. Blood and pancreatic fluid were collected, and the 5-FU concentrations were determined by HPLC assay. Their pharmacoklnetic parameters were obtained by PCNONLIN and statistical analysis was performed. The Cma was 20.03 ± 18.25 mg/l in pancreatic fluid with a Tm,x of 15.6 + 9.5 min following i.v. administration and 49.69 ± 20.75 mg/l in plasma. 5-FU in plasma and pancreatic fluid were all in conformity with a non-linear model with a Km of 1098.08 ±1426.57 and 11.08± 6.38 mg/l, respectively. The concentrations in pancreatic fluid were similar to that observed in plasma with an average penetration index up to 1.01 ±0.49. It is suggested therefore that 5-FU is capable of penetrating from blood into the pancreas as evidenced by the observed pancreatic concentrations.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

We evaluated the pharmacokinetics of 5-fluorouracil (5-FU) combined with recombinant human interferon (IFN)-α2a in 10 previously untreated patients with advanced colorectal carcinoma. 5-FU was administered as a continuous i.v. infusion, 750 mg/m2/day for 5 days during week 1. One s.c. injection of IFN-α2a, 9 × 106IU, was administered during week 2. Beginning with week 3, a continuous i.v. infusion of 5-FU 750 mg/m2/day for 5 days was administered in combination with IFN-22a, 9 × 1 06IU s.c. three times per week. The combination of 5-FU and IFN-α2a was continued every other week until either 3 months after complete remission or tumor progression. No grade 4 toxicity was observed. Granulocytopenia (two patients), leukopenia (one patient), thrombocytopenia (one patient), stomatitis (two patients), fatigue (one patient) and hand-foot syndrome (one patient) were the major (grade 3) toxic reactions encountered. Overall, one complete and six partial responses were noted. The results of the paired t-test showed no statistically significant differences between the means of the two treatments, 5-FU and 5-FU plus IFN-α2a, with respect to the steady-state plasma concentration, area under the concentration-time curve, total body clearance, or steady-state volume of distribution of 5-FU, or the serum concentration of IFN. We conclude that 5-FU and IFN-α2a do not interact pharmacckinetically at the doses and schedules in the regimen studied.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

New cytotoxics with significant activity both in preclinical and clinical situations continued to be applied in the clinic by empiric means. The use of defined cell lines allows unanticipated antagonism between agents to be identified and to suggest synergistic combinations which need to be tested. By means of a semi-automated MTT assay and median effect analysis, we have identified antagonism in two couplets being evaluated in the clinic: etoposide with paclitaxel and vinorelbine with gemcitabine. Optimal use of these agents in man may require spacing these agents in time to prevent an adverse drug interaction between the agents which may diminish the potential response rate.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Resistance of tumor cells to chemotherapeutlc agents is a major problem in cancer therapy. Continuous exposure of human histiocytic lymphoma U-937 cells to 9-nitro-camptothecin (9NC), an inhibitor of the nuclear DNA topoisomerase I, induces resistance to this drug. Because of the involvement of the nuclear factor NF-κB in the expression of several growth regulatory genes, we examined the activation of this transcription factor in 9NC-resistant U-937 cells. We found that resistance to increasing concentrations of 9NC correlated with resistance to tumor necrosis factor (TNF)- dependent activation of NF-κB. However, the constitutive synthesis of NF-κB proteins remained unaffected. Cellular resistance was not unique to TNF, as other activators of NFKB, including lnterleukin-1, phorbol ester and hydrogen peroxide, also had no effect. There was no difference between 9NC-sensitive and -resistant cells in the activation of NF-κB by okadaic acid. Other transcription factors, including AP-1 and Oct-1, were not affected in the resistant cells. When examined for the inhibitory subunit of NF-κB (IκBα), resistant cells showed a faster rate of resynthesis than the control. Interestingly, although 9NC resistance correlated with resistance to TNF-dependent NF-κB activation, TNF-dependent cytotoxicity in these cells was enhanced by several hundred fold despite a significant decrease in the number of TNF receptors. In conclusion, our results suggest that NF-κB activation may play a role in tumor cell killing by 9NC but not by TNF.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Heavy water (deuterium oxide: D2O) contains a neutron and a proton in its hydrogen atoms and shows a variety of biologic activities different from normal light water. In the present study the cytotoxic and cytostatlc activity of D2O was assessed using a BALB/c-3T3 fibroblast cell line and four human digestive organ cancer cell lines, i.e. HepG2 hepatic, Panc-1 pancreatic, KATO-3 gastric and Colo205 colonic cancer cell lines. Against four cancer cell lines, D2O showed significant cytotoxic and cytostatlc effects in a MTT assay and a Trypan blue dye exclusion assay, at concentrations higher than 30% D2O. These effects were time and dose dependent, and the IC50 after 72 h of culture ranged from 20 to 30% D2O in the Trypan blue dye exclusion assay and from 30 to 50% D2O in the MTT assay. By contrast, ICS0 for the 3T3 fibroblast cell line after 72 h of culture was about 15% in the Trypan blue dye exclusion assay and 50% inhibition was not achieved in the MTT assay. Furthermore, D2O was found to significantly Inhibit the invasion of tumor cells in a Matrigel Invasion chamber assay at concentrations higher than 10% D2O. Incubation with D2O resulted in enlargement of cells, nuclear pyknosis and vacuolization, and immunostaining studies demonstrated that D2O treatment resulted in an increase in nuclear nick-end-labeling, which indicates DNA fragmentation, in KATO-3 and HepG2 cell lines. Furthermore, the nucleic acids and protein synthesis inhibition assay suggested that the inhibition of DNA synthesis may be one of the mechanisms responsible for the antitumor effects of D2O. Furthermore, oral administration of D2O resulted in a significant inhibition of the growth of Panc-1 tumor xenografted s.c. in nude mice, but survival was not prolonged. In conclusion, D2O has cytotoxic and cytostatic activities against human digestive organ cancer cell lines, and D2O may be a potential anticancer agent.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Precursor 2'-deoxythymidine 5'-monophosphate for DNA biosynthesis Is supplied by thymidylate synthase (TS) (EC 2.1.1.45) through a denovopathway and the enzyme levels are elevated in malignancy. TS is therefore a key target for cancer chemotherapy. Human leukocyte TS levels in patients with chronic myeloblastic leukemia (CML) and acute lymphoblastic leukemia (ALL) are highly elevated (66- and 33- fold, respectively) compared to the low baseline activity of normal healthy controls. Preliminary screening tests for the antitumor activity of theβ-carboline-benzoquinolizidine alkaloid deoxytubulosine (DTB) (isolated from the Indian medicinal plantAlanguim lamarcktii) were performed employing Invitroinhibition studies on the leukemic leukocyte TS as the probe enzyme. Enzyme activity of the leukemic leukocytes was potently inhibited by DTB (IC50=50µM) In both CML and ALL. The emetine alkaloid DTB was assessed for its biochemical and biological evaluation for the first time as a potential antileukemic agent.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Megestrol acetate (MGA) is being widely used for the improvement of appetite and performance status in patients receiving chemotherapy, especially cisplatin-containing therapy. However, little is known about whether MGA has an effect on cisplatin cytotoxicity. We have investigated this using two transitional carcinoma cell lines, i.e. the cisplatinsensitive parental line NTUB1 and the resistant daughter line NTUB1/P. Combined effects of MGA and cisplatin were assayed with a microculture chemosensitivity method. We explored the level changes of several cisplatin detoxification mechanisms, including metallothionein (MT), glutathione Stransferase- π (GST-π ) and glutathione (GSH) levels in cells treated with or without MGA. After treatment with 10µm MGA for 24 h, the cisplatin IC50s of NTUB1 and NTUB1/P increased 1.4- (p=0.03) and 1.6- (p=0.02) fold, respectively. By median effect analysis, the combinations of MGA and cisplatin in the two cells appeared to produce an antagonistic interaction. By Northern analysis, MT transcript levels in both cells were significantly upregulated after treatment with MGA, as compared to those without treatment. Exposure to MGA in either sensitive or resistant cells did not alter GST-n levels as shown by immunoblotting analysis. Cellular GSH content was increased only in NTUB1/P (p=0.0036) but remained unchanged in NTUB1 cells (p=0.29) after MGA exposure. In conclusion, MGA may antagonize cisplatin cytotoxicity by upregulating cellular MT and GSH levels. Use of MGA in cisplatin-containing chemotherapy may impair tumor response by antagonizing cisplatin antitumor activity.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Explants of highly metastatic human renal cell carcinoma SN12Cpm6 cells In athymic mice were treated with sodium D-glucaro-δ-lactam; (sodium 5-amino-5-deoxy-D-glucosaccharic acid-δ-lactam; ND-2001). ND-2001 (50µg/ml) caused 78% inhibition of lung metastasis of SN12Cpm6 cells (two of five animals remaining metastasis free). TheIn vitrotumor cell invasion assay showed that ND-2001 (100µg/ml) suppressed the invasive activity of SN12Cpm6 cells to Matrigel matrix at an inhibition rate of 72%. These results suggest that ND-2001 may be a new anti-metastatic drug against human cancer cells.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID