摘要:

The 1990s have already heralded an enormous expansion of our knowledge of DNA repair. Gene by gene, protein by protein, each partner in the molecular processes of DNA repair is being identified and characterized, not only in bacteria and yeast, but also in mammalian cellular systems. Several distinctive mechanisms are now explained at a molecular level, even if certain specific parts still remain to be elucidated fully. The techniques used to study DNA repair have also profited from this progress with a plethora of novelin vitroassays, specific antibodies, together with DNA or RNA probes becoming available. The increased use of these tools has permitted a multiplicity of studies on DNA repair which are now not exclusively mechanistically based. Thus, certain studies have now implicated DNA repair processes as likely to be involved in the multifactorial phenomenon of drug resistance to anticancer drugs. Under these circumstances, DNA repair mechanisms should provide useful pharmacological targets to attack with novel inhibitors, with the aim of reducing and/or sensitizing tumor cells to anticancer drugs which damage DNA. Our increased knowledge of the molecular mechanisms associated with DNA repair permits us now to consider such new pharmacological targeting. In this article, we review the present status of these DNA-repair-related pharmacological studies, and discuss both the likely and possible approaches which might have potential therapeutic applications.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

DNA adducts formed by cisplatin [cis-diamminedichloroplatinum (ll)] were measured in blood samples from 48 testicular cancer patients treated in four centers in Europe during four to six cycles with cisplatin infusions on five successive days (total samples, 112). Total protein-bound platinum (Pt) in blood was also measured (total samples, 84). The mean on the main DNA adduct,cis-Pt(NH3)2d(pGpG) (Pt-GG), was 0.75 fmol/μg DNA [standard deviation (SD) = 0.66] on the first day of the first cycle, increased after the infusion at day 5 of the cycle (mean 1.74 fmol/μg DNA, SD = 0.90) and decreased on the following day (mean 1.09 fmol/μg DNA, SD = 0.62). In subsequent cycles, there was a tendency to an increase in the mean Pt-GG levels. The values of protein-bound Pt in blood showed little reduction between day 5 and 6 of each cycle, and a stable increase during the course of the therapy. Strong correlations were seen between day 1, 5 and 6 of the first cycle for both Pt-GG and protein-bound Pt in blood. A strong correlation (r= 0.62,p< 0.001, 69 pairs) was found between the levels of Pt-GG and protein-bound Pt. Only two patients relapsed during the follow-up; therefore, the analysis of the association between Pt-GG levels and response to therapy was not informative. The results of this study suggest that DNA adducts formed by cisplatin at the beginning of chemotherapy are predictive of values found during later days and cycles, and that the value of protein-bound Pt in blood is predictive of the value of DNA adducts.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

This study is based on 194 patients with primary breast cancer treated with adjuvant CNF combination chemotherapy, who were followed-up for the risk of subsequent neoplasms. During an average follow-up of 4.8 years, 16 cases of new cancers were detected. Nine non-breast cancers were observed versus 2.2 expected (standardized incidence ratio 4.2). Of the patients with subsequent malignancies, 88% had received antiestrogen (chemohormonal adjuvant therapy); the percentage among all patients was 25%. We conclude that the benefit derived from adjuvant therapy of breast cancer may be reduced because of an increased risk of subsequent cancers.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Patients with non-Hodgkin's lymphoma (NHL) recurrent after chemotherapy exhibit clinical characteristics compatible with the phenomenon of multidrug resistance (MDR) and frequently have detectable levels of P-glycoprotein (P-gp). Paclitaxel has been used in recurrent NHL with limited success. To test whether clinical resistance to paclitaxel can be reversed, we treated patients having paclitaxel-resistant NHL with paclitaxel plus quinine and measured the effects of quinine on paclitaxel pharmacokinetics. Eligible patients had recurrent and measurable NHL. Patients initially received paclitaxel, 120 mg/m2(dose determined by a phase I trial of paclitaxel plus quinine), as a 20–24 h infusion every 3 weeks until there was evidence of clinical resistance. Patients then received paclitaxel at the same dose rate plus oral quinine at a fixed dose rate of 400 mg three times each day. Paclitaxel pharmacokinetics were studied in each patient using paired samples from plasma obtained at the end of the 24 h paclitaxel infusion as an estimate of the steady-state drug level. Of 14 patients treated with paclitaxel alone, one patient obtained a partial response (7%). At the time of disease progession, one patient (same patient) obtained a partial response with paclitaxel plus quinine (7%). Steady-state paclitaxel levels were obtained in 12 patients. In 11 of 12 patients the steady-state paclitaxel level was substantially lower with the addition of quinine. The average ratio of end of infusion plasma levels (paclitaxel alone/paclitaxel plus quinine) was 0.6 (range 0.31–0.97) indicating a 40% decrease in paclitaxel levels with the addition of quinine (p= 0.001). We conclude that paclitaxel given by this dose and schedule has modest activity in recurrent NHL. The addition of quinine to paclitaxel also has limited activity, but the combination did reverse paclitaxel resistance in one patient, adding support to the hypothesis that clinical drug resistance can be overcome with chemosensitizers in individual patients. Pharmacokinetic studies indicate that the reversal of drug resistance in this study cannot be attributed to changes in clearance of paclitaxel (which appears to increase with quinine), but more likely to the sensitization of lymphoma cells.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Glucosinolates hydrolysis products are attracting increasing attention since many studies have suggested that they may be involved in the anticarcinogenic property of cruciferous vegetables. In this study, we show that diindolylmethane (DIM) and sulforaphane, produced during the hydrolysis of glucobrassicin and glucoraphanin, respectively, exert a dose-dependent cytotoxicity on human colon adenocarcinoma HT29 cells. Moreover, these products are able to inhibit quiescent cells to re-enter the cell cycle. Interestingly, our results clearly show that low doses of DIM and sulforaphane, although very effective on undifferentiated intestinal HT29 cells, do not affect the viability of the differentiated CaCo2 cells. The reversibility of their effects has also been tested and is discussed.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

We studied the antitumor effects of dolastatin 10, its structural modification, auristatin PE (TZT-1027), and vincristine alone and in combination with bryostatin 1 on a human diffuse large cell lymphoma line (WSU-DLCL2) in vitro andin vivo.WSU-DLCL2cells were cultured in RPMI 1640 at a concentration of 2 × 105/ml using a 24-well plate. Agents were added to triplicate wells, and cell count, viability, mitosis and apoptosis were assessed. Dolastatin 10 showed no apparent inhibition of cell growth at concentrations less than 500 pg/ml. Auristatin PE showed significant growth inhibition at concentrations as low as 10 pg/ml, while vincristine had a minimal effect at 50 pg/ml. Dolastatin 10, auristatin PE and vincristine-treated cultures, at 50 pg/ml, exhibited 11, 1.7; 45, 11.8%; and 39, 25% mitosis and apoptosis, respectively. In the WSU-DLCL2SCID mouse xenograft model, the efficacy of these agents alone or in combination with bryostatin 1 was evaluated. Tumor growth inhibition (T/C), tumor growth delay (T-C) and log10kill for dolastatin 10, auristatin PE, vincristine and bryostatin 1 were 30%, 14 days and 1.4; 0.0%, 55 days and 5.5; 29.6%, 16 days and 1.6; and 39%, 7 days and 0.7, respectively. When given in combination, two out of five mice treated with auristatin PE + bryostatin 1 were free of tumors for 150 days and were considered cured. Dolastatin 10 + bryostatin 1 and vincristine + bryostatin 1 combinations were highly active but no cure was observed. We conclude that: (i) auristatin PE is more effective in this model than dolastatin 10, vincristine or bryostatin 1, (ii) auristatin PE can be administered at a concentration 10 times greater than dolastatin 10, and (iii) there is a synergistic effect between these agents and bryostatin 1, which is more apparent in the bryostatin 1 + auristatin PE combination. The use of these agents should be further explored clinically in the treatment of lymphoma.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The present study was performed to evaluate the ability of KR-30032 and KR-30035 to overcome multidrug resistance (MDR) by measuring the cytotoxicity and the accumulation rate of rhodamine. Additionally, the adverse cardiac toxicity of KR-30032 and KR-30035 was evaluated by measuring the changes of tension in isolated rat aorta and left ventricular pressure (LVP) in guinea pig heart. KR-30035 potentiated the paclitaxel-induced cytotoxicity to HCT15 [P-glycoprotein (P-gp)-expressed cells] to over 15-fold greater than that of verapamil and KR-30032 was equipotent with verapamil (EC50: 0.07, 5.0 and 3.3 μM at 1.0 μg/ml). KR-30032 and KR-30035 were without effect on cytotoxicity to SK-OV-3 cells (P-gp-non-expressing cells), as well as to tamoxifen-induced cytotoxicity in the above cell types. Maximal rhodamine accumulation rates with KR-30032, KR-30035 and verapamil were 290, 291 and 271% in HCT15 cells; and 451, 970 and 440% in HCT15/CL02 cells, respectively. KR-30032 and KR-30035 were 20-to 25-fold less potent than verapamil in relaxing aorta (EC50: 8.13, 6.40 and 0.32 μM, respectively) and were 12-to 35-fold less potent than verapamil in decreasing LVP in isolated hearts (EC50: 41.8, 14.1 and 1.2 μM, respectively). The results of this study suggest that KR-30032 and KR-30035 are active modulators of MDR with potentially minimal cardiovascular toxicity.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Trans-bis(n-valerato)(1R,2R-cyclohexanediamine)(oxalato)-platinum (IV) (C5-OHP) is an orally active platinum complex we prepared. The gastrointestinal absorption of C5-OHP was examined in rats and compared with those of C5-OHP analogs which have a general formula oftrans-bis(n-OCOCnH2n+1)(1R,2R-cyclohexanediamine)(oxalato)platinum (IV) as well as C5-OHP. The complexes did not show significant differences in pharmacokinetic behavior after i.v. injection. Plasma platinum level after a single oral administration at a dose was higher for a complex with higher water solubility. The intestinal absorption rate measured by an in situ recirculating perfusion technique was higher for a complex with higher lipophilicity. These results indicate that the water solubility is a more dominant factor than the lipophilicity in the gastrointestinal absorption of the complexes. Then, the effects of surfactants andx-cyclodextrin (x-CD) on the solubility of C5-OHP was studied. Among the agents tested,x-CD showed the highest effect in increasing the solubility. Administration of C5-OHP together withx-CD gave approximately three times higher plasma platinum levels than administration of C5-OHP alone. Water solubility was found to be a dominant factor in the gastrointestinal absorption of C5-OHP and its analogs.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Thein vitrochemosensitivity of three cancer cell lines [HT29 (colon), HeLa (cervical) and T47D (breast)] to eight synthetic tetrapeptides, analogs of AS-I toxin, with phytotoxic effect on a series of plants was studied. Mouse fibroblast L929 cell line was also tested for chemosensitivity to these peptides. All cell lines were especially sensitive to Cys-Val-Gly-Glu tetrapeptide with IC50values of 0.18, 0.3 and 0.63 mM for HT29, HeLa and T47D cells, respectively, whereas the IC50value for the L929 cells was higher than 1 mM. Antiproliferative activity was also observed with peptides Tyr-Val-Gly-Glu and His-Val-Gly-Glu with IC50values higher than those obtained for Cys-Val-Gly-Glu. For the rest of the peptides tested the IC50values were found close to or higher than 3 mM.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The purpose of the present study was to evaluate the tissue distribution of toremifene (TOR) in baboons following intra-tissue injections and to examine the effectiveness of intratumoral TOR therapy of baboons with various spontaneous neoplasms. Five healthy baboons (Papiosp.) were used to examine the distribution of TOR following intra-tissue injections. Twenty-three different tissue specimens were collected for HPLC analysis. In addition, four baboons with various spontaneous neoplasms (myxoma, squamous cell carcinoma, lymphosarcoma and adenocarcinoma) were treated with intratumoral TOR and their responses were evaluated. Tissue TOR distribution was also examined In these animals. In the tissue distribution study, target tissue/serum TOR concentration ratios ranged from 138 to 8873 and the target tissue/other tissue ratios ranged from 1.2 to 2428. The distribution of TOR was very favorable, with the highest concentrations outside the injection sites noted in adjacent organs. A marked response was observed in the myxoma and partial responses were observed in the other three cases. Drug level analysis data from these four animals revealed tissue concentrations similar to those seen in the TOR tissue distribution study. Intratumoral administration of TOR can achieve effective local tumor and tissue concentrations, while systemic distribution via circulation to other organs is limited.

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID