摘要:

Gemcitabine is a novel nucleoside analog with demonstrated efficacy across a range of solid tumors. This paper reviews the single-agent safety profiles of 979 patients in 22 completed clinical studies using a day 1, 8, 15 q 28 day, 800–1250 mg/m2dose schedule. Hematological toxicity was mild with WHO grade 3 and 4 toxicities recorded for hemoglobin (6.8 and 1.3% of patients), leukocytes (8.6 and 0.7%), neutrophils (19.3 and 6.0%) and platelets (4.1 and 1.1%). Myelosuppression was short lived and rarely of clinical significance. Mucositis and alopecia were rare, and nausea and vomiting mild. Transient rises in transaminases, mild proteinuria and hematuria were common, but rarely clinically significant. Renal failure of uncertain etiology was reported in seven instances. Some patients (18.9%) experienced transient flu-like symptoms and mild fever was reported in 37.3% of flu patients. Peripheral edema was reported in 20.3% of patients in the absence of cardiac, hepatic or renal failure. Thus, gemcitabine is well tolerated and has a mild toxicity profile. Of nearly 11000 protocol-defined injections, 94% were administered and only 14% were reduced. Grade 3 or 4 non-laboratory toxicities with a frequency of more than 1% were only seen for infection (1.2%), nausea and vomiting (18.4%), and pulmonary toxicity (1.4%).

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Results from our previous phase II study demonstrating high efficacy and low toxicity for a weekly schedule of 5-fluorouracil (5-FU)/leucovorin in intensively pretreated patients with metastatic breast cancer prompted addition of paclitaxel and cisplatin to this regimen for a phase II study of outpatient first-line treatment of metastatic breast cancer. (MBC). Twenty-eight patients with metastatic breast cancer have been evaluated. Pretreatment comprised adjuvant CTX in 24 out of 28 patients, but no prior CTX for MBC. Patients were treated with 5-FU 2 g/m2(24 h infusion) plus leucovorin 500 mg/m2(2 h infusion prior to 5-FU) weekly for 6 weeks (days 1, 8, 15, 22, 29 and 36); in addition, paclitaxel 175 mg/m2(3 h infusion) was administered on days 0 and 21, and cisplatin 50 mg/m2(1 h infusion) on days 1 and 22 prior to 5-FU/leucovorin, repeated every 50 days. All patients were treated as outpatients using Port-a-Cath systems and portable pumps. Aside from common total alopecia, neutropenia was common but only of short duration. No episodes of febrile neutropenia occured. Non-hematologic toxicities (NCl CTC grade, percent of patients) consisted of mild to moderate diarrhea (2+3, 47%), mucosits (2, 14%), and nausea and vomiting (2+3, 60%). Out of 28 patients with bidimensionally measurable disease 25% (seven out of 28) achieved a CR, 57% (16 out of 28) achieved a PR, 11% (three out of 28) had a SD and 7% (two out of 28) had a PD. Overall RR was 82% (95% confidence interval 66–100%). Median remission duration was 8 months, median time to progression 9 months and median survial time 28 months with a median follow-up of 21 months. We conclude that the combination of paclitaxel, cisplatin and 5-FU/leucovorin is an effective non-anthracycline-containing regimen for the first-line treatment of MBC.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The cytotoxicity of sequential combinations of a taxoid [paclitaxel (TAX) or docetaxel (TXT)] with a vinca alkaloid [vinoreibine (NVB)] was compared in differentiated and undifferentiated HT29-D4 cells. Agents were titrated from low doses inducing no modification of microtubule network to high doses corresponding to the clinically relevant concentrations that block mitosis. For undifferentiated cells, the sequential combination NVB/TAX was more efficient than TAX/NVB (22% cell survival versus 37% for 5 nM TAX and NVB). Surprisingly, we successively obtained synergism for low doses of both compounds [NVB (1–5 nM) and TAX (1–15 nM)], then additivity and finally antagonism when one of the compounds was at the concentration inducing mitotic block. The three patterns of results were also obtained with NVB/TXT combinations. For the synergistic combinations at the lowest concentrations, cytotoxicity occurred by apoptosis following mitosis. For differentiated cells, the most cytotoxic combinations were 1 μM TAX or TXT for 3 days followed by 1 μM NVB for 3 days, and 0.75 nM TAX or TXT for 9 days followed by 1 μM NVB for 3 days, the latter producing synergistic effects. Cytotoxicity occurred by apoptosis for the two states of differentiation. Major differences depending on cell phenotype were demonstrated: low sensitivity of differentiated cells to antitubulin agents and the difference in apoptotic pathways since mitosis is not involved in differentiated cells.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Variations in plasma protein binding may have profound effects on both disposition and activity of drugs, especially for those which are tightly bound to proteins, such as anticancer platinum derivatives. Methods of separation of the non-protein-bound fraction and some technical parameters may influence the results. We have compared ultrafiltration and ultracentrifugation, as well as the effect of potentially interfering factors, upon the determination of the plasma unbound platinum fraction after oxalipiatin administration to cancer patients. Ultrafiltration and ultracentrifugation provided very closely correlated results, so that either technique can be used. The ultrafiltration cut-off (3000–30 000 Da) devices, the type of tube for blood sampling and the type of anticoagulant (none, lithium heparinate or EDTA) did not influence the results markedly. In contrast, results were greatly influenced by freezing: erratic results were obtained on thawed plasmas when compared with those on fresh serum or plasma. Consequences may be important in usual practice, since many pharmacokinetic studies are carried out in multicentric trials with plasma processing centralized in one reference laboratory. The methods for the determination of protein-drug binding should be standardized and guidelines elaborated where optimal conditions for each type of binding assay are given.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Ovarian cancer has a poor prognosis due to the frequent appearance of a drug-resistant state. An alternative therapeutic approach may lie in combinations of conventional chemotherapeutic agents with new classes of drug, such as interferons (IFN) and differentiation-inducing agents. There is clinical evidence that both IFN-α2a–all-transretinoic acid (ATRA) and IFN-α2a–cisplatin have significant activities on growth of malignant cells, cell differentiation or programmed cell death in solid tumors. In order to throw more light on the cellular basis of these findings and to optimize a schedule of such drug combinations, we examined the cytotoxic effects of various combinations on five human ovarian carcinoma cell lines. The experiments were based on a clonogenic assay on plastic. The different cell lines exhibited different sensitivities to the three drugs tested. Using the cell line most sensitive to these drugs, we then examined the effect of different sequences of two drug combinations. We observed a potentiation after pretreatment with ATRA followed by IFN-α2a and ATRA or after pretreatment with IFN-α2a followed by IFN-α2a and cisplatin. Using this schedule of administration, cytotoxic interactions between the two drugs were investigated by median effect analysis. Synergism or antagonism were observed depending on the intrinsic sensitivity of the cell line to the first drug and the concentrations used. The magnitude of these interactions was found to be influenced by the cellular sensitivity to the second drug. These results show that schedules of drug combinations are not easy to design and may help account for the various failures and the discrepant effects observed in clinical trials.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Nitrosylcobalamin, a vitamin B12-based, non-toxic carrier of nitric oxide (NO), has been synthesized, isolated and characterizedIn vitro.A UV/Vis analysis was performed confirming the reduction of the cobalt atom of hydroxocobalamin (vitamin B12a) with the binding of NO, causing a shift in the absorption spectra of Co3+(Λmax=530) to Co2+(Λmax=500) with the formation of nitrosylcobalamin. The extinction coefficient (εmax) of nitrosylcobalamin, as calculated, was 4.8 (mM-1cm-1). An IR analysis determined thev(NO) vibrational frequency at 1652 cm-1, supporting the binding of NO and suggesting a bent bonding geometry. NO release was maximized utilizing acidic conditions (pH 4.9, 32°C) with a cumulative release of about 4610 nmol of NO in 675 h (calculated half-life of 210 h), representing 39% NO loading based on 11890 nmol NO, theoretically possible (one NO per molecule of hydroxocobalamin). The cumulative NO release followed first-order kinetics and was pH dependent. NO release was minimal at pH 6.0 and 7.4 (37°C), and undetected at pH 10 (37° C). The possibility for nitrosylcobalamin to deliver NO (the active chemotherapeutic agent) to neoplastic cells is suggested because tumor cells, specifically leukemia cells, possess surface cell receptors for vitamin B12 which is readily utilized in the cellular proliferation process. Nitrosylcobalamin may offer a ‘drug targeting’ approach as a potential, biologically compatible and selective chemotherapeutic agent.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

We have evaluated the effect of two topoisomerase II (Topo II) poisons, amsacrine and doxorubicin, on the expression of the c-myconcogene, both at the mRNA and protein levels, in the leukemia cell line, K562, and its doxorubicin-resistant counterpart, K562 DoxR. We report in this study a concentration-dependent decrease in c-mycmRNA levels upon exposure of both cell lines to amsacrine and doxorubicin, with a more pronounced effect for amsacrine in the resistant line. In either case, c-mycdown-regulation closely paralleled the drug-induced growth inhibition. We have also used the technique of PCR stop-assay to detect the occurrence of DNA breaks within the P2 promoter of the c-mycgene. We have shown that Topo II-mediated breaks induced by amsacrine are probably responsible for the down-regulation of c-mycin the resistant line. In addition, amsacrine induced apoptosis only in the resistant line while doxorubicin did not induce apoptosis in any cell line. These results suggest that c-mycis not involved in the resistance of K562 DoxR cells, but can induce the apoptosis pathway in these cells, while no drug-induced apoptosis could be detected in the sensitive line.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The occurrence of resistance to chemotherapeutic drugs is a major problem for successful cancer treatment and reducing drug accumulation by P-glycoprotein (P-gp) is one of the major mechanisms of multidrug resistance (MDR). The present study was performed to evaluate the MDR-reversal abilities of twobisbenzylisoquinoline alkaloids, tetrandine (TET) and fangchinoline (FAN), compared with verapamil (VER), a well-known P-gp modulator. TET (3.0 μM), FAN (3.0 μM) and VER (10.0 μM) reduced the paclitaxel (TAX) concentration required to achieve 50% inhibition of cell growth (EC50) to HCT15 (P-gp-positive) cells about 3100-, 1900− and 410-fold, and these compounds also reduced the EC50 value of actinomycin D (AMD) about 36.0-, 45.9− and 18.2-fold in the cells, respectively. Meanwhile, TET, FAN and VER had no effect on the cytotoxicity of the drugs to SK-OV-3 (P-gp-negative) cells. On the other hand, TET (3.0 μM), FAN (3.0 μM) and VER (10.0 μM) similarly enhanced the accumulation rates of rhodamine 123, a well known P-gp substrate, in HCT15 cells (200–250%). After efflux for 2 h with fresh medium, TET and FAN also enhanced the residual rate of rhodamine 123 about 5.0− and 2.6-fold in comparison with control, respectively. TET, FAN and VER could not affect the accumulation and residual rate of rhodamine 123 in SK-OV-3 cells. From the result, we conclude that TET and FAN enhanced the cytotoxicity of MDR-related drugs via modulation of P-gp.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

5-(3-Aminopropyl)amino-7,10-dihydroxy-2-(2-hydroxethyl)-aminoethyl-6H-pyrazolo[4,5,1-de]acridin-6-one dihydroxychloride (KW-2170), a novel derivative of pyrazoloacridone, was selected and evaluated for its antitumor activity and toxicity in mice. KW-2170 exhibited antitumor activity superior to adriamycln (ADM) against Sarcoma 180, breast carcinoma MM102 and fibrosarcoma Meth A inoculated s.c. in mice. Its therapeutic index (LD10/ED50) was higher than that of ADM on two murine carcinoma models, MM102 and Meth A. KW-2170 showed significant antitumor activity against 17 human tumor xenografts of a total of 24 tumors tested and the total tumor response rate by treatment with KW-2170 was significantly higher than that by ADM (70.8 versus 58.3%). In particular, human lung carcinoma was highly sensitive to KW-2170, and a marked tumor regression was observed on Lu-65 and Lu-99 human lung carcinoma xenograft models. Ovary and pancreas carcinomas were also sensitive to the drug. Additionally, its therapeutic index was also high on these human carcinoma models in comparison with that of ADM. The best antitumor efficacy of KW-2170 was observed by a weekly treatment schedule followed by a single treatment schedule and a successive administration schedule also tended to be toxic to the hosts. KW-2170 exhibited very low cross-resistance against four lines of multidrug resistant tumors expressing high levels of P-glycoprotein, and the drug showed significant antitumor activity against ADM-resistant human ovary carcinoma A2780/ADM and against nasopharynx carcinoma KB-A1 xenografts which were not sensitive to ADM. These results indicate that KW-2170 has a very potent antitumor activity and is feasible as a new antitumor drug against ADM-refractory solid tumors in clinics.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

We investigated the therapeutic effects of ONO-4007, a novel synthetic lipid A derivative with low toxic activities, on transplanted hepatocellular carcinoma KDH-8 in WKAH rats. ONO-4007 brought about complete cures in about 60% of rats bearing tumor necrosis factor (TNF)-α-sensitive KDH-8 cells, whereas no complete cure was observed in rats bearing cKDH-8/11 which is identical to KDH-8 but a TNF-α-resistant cell line, KMT-17 and KEG-1. Then we examined the influence of rabbit anti-TNF-α antibody on the therapeutic effects of ONO-4007 against the TNF-α-sensitive KDH-8. The concomitant administration of the rabbit anti-TNF-α antibody completely abrogated the therapeutic effects of ONO-4007. On the other hand, rechallenged tumor cells of both KDH-8 and cKDH-8/11 were completely rejected in the rats cured of KDH-8 tumor, although no rejection of KEG-1 was observed. Moreover, Winn assay, i.e. the tumor cell neutralizing assay, indicated that CD4+T cells were involved in the antigen-specific transplantation resistance. These findings suggest that antigen-specific T cell responses are involved in the complete cure of tumors after the treatment with ONO-4007, although its therapeutic effect is initiated by TNF-α.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID