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E Boven

Publications and source records attributed to E Boven.

At least 19 recordsLinked to original sources
PubMed2006

CD13/Aminopeptidase N overexpression by basic fibroblast growth factor mediates enhanced invasiveness of 1F6 human melanoma cells.

CD13/Aminopeptidase N (CD13) is known to play an important role in tumour cell invasion. We examined whether basic fibroblast growth factor (bFGF) is involved in the regulation of CD13 expression in human melanoma cells. 1F6 human melanoma cells were stably transfected with constructs encoding either the 18 kDa (18 kD) or all (ALL) bFGF isoform proteins. We observed highly increased CD13 mRNA and protein expression in the 1F6 clones regardless of the overexpression of either the 18 kD or all isoform proteins. Neutral aminopeptidase activity was increased five-fold and could be inhibited by bestatin and the CD13-neutralising antibody WM15. The enhanced invasion through Matrigel, but not migration in a wound assay, was efficiently abrogated by both bestatin and WM15. Upregulation of CD13 expression was the result of increased epithelial and myeloid promoter activity up to 4.5-fold in 1F6-18 kD and 1F6-ALL clones. Interestingly, in a panel of human melanoma cell lines, a significant correlation (r(2)=0.883, P<0.05) between bFGF and CD13 mRNA and protein expression was detected. High bFGF and CD13 expression were clearly related with an aggressive phenotype. Taken together, our data indicate that high bFGF expression upregulates CD13 expression in human melanoma cells by activating both the myeloid and the epithelial CD13 promoter. In addition, we show that high bFGF and CD13 expression results in enhanced invasive capacity and metastatic behaviour of human melanoma cells.

CD13 Antigens↗
PubMed2005

Recombinant human endostatin administered as a 28-day continuous intravenous infusion, followed by daily subcutaneous injections: a phase I and pharmacokinetic study in patients with advanced cancer.

BACKGROUND: Endostatin is an endogenous collagen XVIII-fragment with anti-angiogenic properties and remarkable antitumor activity in mice. Preclinical data suggest that continuous low dose administration of endostatin is much more potent than intermittent dosing. The feasibility of this approach is tested in a phase I study. PATIENTS AND METHODS: We determined the safety and pharmacokinetic profile of 4-week continuous intravenous infusion of recombinant human (rh)-endostatin, followed after an interval of 1 week by twice daily subcutaneous injections in patients with advanced cancer. Thirty-two patients received rh-endostatin in six dosing cohorts, ranging from 3.75 mg/m(2)/day to 120 mg/m(2)/day. Serum endostatin pharmacokinetics, toxicity and antitumor response were determined. RESULTS: A total of 160 cycles were delivered without significant toxicities. Pharmacokinetic analysis showed a linear increase of steady-state serum endostatin concentrations with dose (i.v. r(2)=0.96; s.c. r(2)=0.99) reaching 300--1,000 ng/ml for the two highest doses, with considerable interpatient variation. The main pharmacokinetic values for both routes of administration were similar. The apparent steady-state concentration and AUC reached at 60--120 mg/m(2)/day were within the range expected to induce anti-angiogenic and antitumor effects based on preclinical tumor models. Although no objective responses were observed, two patients had long-lasting stable disease (defined as a tumor increase<100%). CONCLUSION: rh-endostatin was safely administered both by continuous infusion and by twice daily subcutaneous injections up to 120 mg/m(2)/day. Predictable pK was seen in this dose range and the target endostatin levels were reached from 60 mg/m(2)/day and above.

Adult↗
PubMed2005

Phase I and pharmacokinetic study of the novel chemoprotector BNP7787 in combination with cisplatin and attempt to eliminate the hydration schedule.

BNP7787 (disodium 2,2'-dithio-bis-ethane sulphonate; Tavocept) is a novel agent developed to protect against cisplatin (cis-diammine-dichloroplatinum(II))-associated chronic toxicities. In this study, we determined the recommended dose of BNP7787 when preceding a fixed dose of cisplatin, the pharmacokinetics (PKs) and the possible reduction of saline hydration. Patients with advanced solid tumours received BNP7787 in escalating doses of 4.1-41 g m(-2) as a 15-min intravenous (i.v.) infusion followed by cisplatin 75 mg m(-2) as a 60-min i.v. infusion together with pre- and postcisplatin saline hydration in a volume of 2200 ml; cycles were repeated every 3 weeks. PK was carried out using BNP7787, cisplatin and the combination. Twenty-five patients were enrolled in stage I of the study to determine the recommended dose of BNP7787. No dose-limiting toxicity was reached. The highest dose level of 41 g m(-2) resulted in a low incidence of grade 2 toxicities, being nausea and vomiting, dry mouth or bad taste and i.v. injection site discomfort. Doses of BNP7787 > or = 18.4 g m(-2) did not show a drug interaction between BNP7787 and cisplatin. In stage II of the study, patients received a fixed dose of BNP7787 of 18.4 g m(-2) preceding cisplatin and were entered in prespecified reduced saline hydration steps. A total of 21 patients in cohorts of six to nine patients received reduced saline hydration of 1600 ml (step A), 1000 ml (step B) and 500 ml (step C). In step C, two out of six evaluable patients experienced grade 1 nephrotoxicity. Cisplatin acute toxicities in all 46 patients were as expected. Only five patients complained of paresthesias grade 1 and six developed slight audiometric changes. Partial tumour response was observed in four patients and stable disease in 15 patients. In conclusion, BNP7787 was tolerated well up to doses of 41 g m(-2). The recommended dose of 18.4 g m(-2) enabled safe reduction of the saline hydration schedule for cisplatin to 1000 ml. Further studies will assess whether BNP7787 offers protection against platinum-related late side effects.

Adult↗
PubMed2004

Pharmacokinetic behaviour of the chemoprotectants BNP7787 and mesna after an i.v. bolus injection in rats.

In preclinical studies, BNP7787 (disodium 2,2'-dithio-bis-ethane sulphonate), the disulphide form of mesna, has demonstrated selective protection against cisplatin-induced nephrotoxicity due to conversion into mesna inactivating toxic platinum species. Mesna (sodium 2-mercapto ethane sulphonate), however, can affect the antitumour activity of cisplatin, while BNP7787 does not interfere with the antitumour activity. To understand the difference in interference with cisplatin-induced antitumour activity between BNP7787 and mesna as well to characterise the selective nephroprotection by BNP7787, the pharmacokinetics of BNP7787 and mesna, each given i.v. 1000 mg x kg(-1), were determined in plasma, kidney, liver, red blood cells (RBC), skeletal muscle and tumour of Fischer rats bearing subcutaneously implanted WARD colon tumours. The following results were obtained: (1). high concentrations of BNP7787 and mesna were observed in the plasma and kidney after administration of BNP7787 or mesna, except for mesna in plasma after BNP7787 administration; (2). in all other sampled compartments, the AUC values of both compounds were at least 5.5-fold lower than the corresponding values in kidney; (3). the AUC of mesna in plasma after mesna administration was comparable to the AUC of mesna in kidney after a dose of BNP7787 that can completely prevent cisplatin-induced nephrotoxicity in rats; (4). the AUC of mesna in plasma was five-fold higher relative to the AUC of mesna following BNP7787 administration (P<0.01). In conclusion, the five-fold higher AUC of mesna in plasma after mesna administration and the fact that mesna is more reactive with (hydrated) cisplatin than its disulphide form BNP7787 represent a plausible explanation as to why mesna administration can reduce the antitumour activity of cisplatin. After BNP7787 administration, the distribution of BNP7787 and mesna was restricted to the kidney, which confirmed the selective protection of the kidney by BNP7787.

Animals↗
PubMed2004

A phase IIA study of the topoisomerase I inhibitor, exatecan mesylate (DX-8951f), administered at two different dose schedules in patients with platinum- and taxane-resistant/refractory ovarian cancer.

OBJECTIVES: There is an urgent need for new agents with activity in platinum- and taxane-resistant epithelial ovarian cancer. Exatecan mesylate is a novel topoisomerase I inhibitor with potent activity against ovarian cancer in vitro. A multicentre phase IIA study was conducted in patients with platinum- and taxane-resistant epithelial ovarian cancer. PATIENTS AND METHODS: Fifty-seven patients with bidimensionally measurable ovarian cancer, previously exposed to platinum and taxanes, whose disease had relapsed within 6 months of platinum-containing chemotherapy were randomised to one of two intravenous schedules of exatecan mesylate; 0.3 mg/m(2) daily for 5 days every 3 weeks (Arm A) or 2.1 mg/m(2) weekly for 3 weeks out of 4 (Arm B). RESULTS: There were no responses in the weekly arm and a radiological response rate of 5.3% (95% CI 0.3-21.8%) in the daily arm. Principal toxicities were myelosuppression and emesis. Grade 3/4 neutropenia occurred in 29% of patients in Arm A and 6% patients in Arm B. Seventy-one percent of patients in Arm A required red cell transfusions while on treatment. CONCLUSIONS: Exatecan is well tolerated in this poor prognosis group of patients but only has modest single agent activity when administered in a daily regimen.

Adult↗
PubMed2003

Phase I and pharmacokinetic study of the topoisomerase I inhibitor, exatecan mesylate (DX-8951f), using a weekly 30-minute intravenous infusion, in patients with advanced solid malignancies.

BACKGROUND: The topoisomerase I inhibitor exatecan mesylate (DX-8951f ) is a water-soluble hexacyclic analogue of camptothecin that does not require enzymatic activation. This study determined the toxicity, maximum tolerated dose (MTD), pharmacokinetics and pharmacodynamics of a weekly intravenous (i.v.) schedule of DX-8951f. PATIENTS AND METHODS: Thirty-five patients with advanced solid malignancies, stratified as minimally (MP) or heavily (HP) pre-treated, received escalating doses of DX-8951f as 30-min i.v. infusions for three out of every 4 weeks. Pharmacokinetics were described after the first infusion of DX-8951f. RESULTS: Infusions (244) of DX-8951f were administered with a median of two cycles (range 1-10). The main toxicity observed was haematological. There was no significant gastrointestinal toxicity. Two patients (6%) had confirmed partial responses. Twelve patients (39%) had stable disease. DX-8951f had a terminal elimination half-life of approximately 8 h and a clearance of 2 l/h/m(2). The area under the plasma concentration versus time curve (AUC( infinity )) and the maximum plasma concentration (C(max)) increased linearly with the dose. A linear relationship was present for the percentage decrease in neutrophil counts or platelet counts and AUC( infinity ) as well as C(max). CONCLUSIONS: The dose-limiting toxicity of DX-8951f is neutropenia for MP patients and neutropenia and thrombocytopenia for HP patients. Evidence for clinical activity was seen, suggesting phase II study of the drug is indicated. Using this schedule the recommended dose is 2.75 mg/m(2)/week for MP patients and 2.10 mg/m(2)/week for HP patients.

Adult↗
PubMed2002

Induction of breast cancer resistance protein by the camptothecin derivative DX-8951f is associated with minor reduction of antitumour activity.

DX-8951f (exatecan mesylate), a new water-soluble derivative of camptothecin, is currently being evaluated in phase II clinical trials. Resistance may be acquired when treating cancer patients with DX-8951f. Therefore, we selected a subline of the human ovarian cancer cell line A2780 for resistance against DX-8951f to investigate possible mechanisms of resistance. This DX-8951f-resistant subline, designated 2780DX8 (resistance factor=9.3), displayed a typical cross-resistance pattern including compounds, such as topotecan (resistance factor =34), SN-38 (resistance factor =47), mitoxantrone (resistance factor =59) and doxorubicin (resistance factor =2.9), which have previously been associated with the expression of breast cancer resistance protein. 2780DX8 cells did not show changes in the topoisomerase I gene, in topoisomerase I protein levels or catalytic activity. Overexpression of breast cancer resistance protein could be detected, both at the mRNA and protein level, while staining for Pgp, MRP1, or LRP was negative. GF120918, an inhibitor of breast cancer resistance protein, was able to reverse the DX-8951f-induced resistance in 2780DX8 cells. In vivo experiments in well-established 2780DX8 human tumour xenografts demonstrated that the growth inhibition induced by CPT-11 was more affected by breast cancer resistance protein expression than that of DX-8951f. These data indicate for the first time that DX-8951f is able to induce breast cancer resistance protein as a mechanism of resistance. Breast cancer resistance protein, however, results in only minor reduction of antitumour activity of DX-8951f which is an advantage over topotecan and CPT-11/SN-38.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

A fully human anti-Ep-CAM scFv-beta-glucuronidase fusion protein for selective chemotherapy with a glucuronide prodrug.

Monoclonal antibodies against tumour-associated antigens could be useful to deliver enzymes selectively to the site of a tumour for activation of a non-toxic prodrug. A completely human fusion protein may be advantageous for repeated administration, as host immune responses may be avoided. We have constructed a fusion protein consisting of a human single chain Fv antibody, C28, against the epithelial cell adhesion molecule and the human enzyme beta-glucuronidase. The sequences encoding C28 and human enzyme beta-glucuronidase were joined by a sequence encoding a flexible linker, and were preceded by the IgGkappa signal sequence for secretion of the fusion protein. A CHO cell line was engineered to secrete C28-beta-glucuronidase fusion protein. Antibody specificity and enzyme activity were retained in the secreted fusion protein that had an apparent molecular mass of 100 kDa under denaturing conditions. The fusion protein was able to convert a non-toxic prodrug of doxorubicin, N-[4-doxorubicin-N-carbonyl(oxymethyl)phenyl]-O-beta-glucuronyl carbamate to doxorubicin, resulting in cytotoxicity. A bystander effect was demonstrated, as doxorubicin was detected in all cells after N-[4-doxorubicin-N-carbonyl(oxymethyl)phenyl]-O-beta-glucuronyl carbamate administration when only 10% of the cells expressed the fusion protein. This is the first fully human and functional fusion protein consisting of an scFv against epithelial cell adhesion molecule and human enzyme beta-glucuronidase for future use in tumour-specific activation of a non-toxic glucuronide prodrug.

Animals↗
PubMed2002

Time-dependent changes in factors involved in the apoptotic process in human ovarian cancer cells as a response to cisplatin.

OBJECTIVES: Apoptosis is believed to be a major mechanism of cisplatin-induced cell death. We investigated the kinetics of apoptosis in four human ovarian cancer cell lines treated with cisplatin to obtain insight into the role and the behavior of a variety of factors involved in this process. METHODS: The cell lines A2780, H134, and IGROV-1 (all wild-type p53) and OVCAR-3 (mutant p53) were exposed to cisplatin for 1 h and the antiproliferative effects were measured after 96 h. At various time points up to 96 h after the 1-h exposure to the individual 90% growth-inhibiting cisplatin concentrations, FACS analysis and May-Grünwald Giemsa staining were carried out to determine the extent of apoptosis. At the same time points protein expression levels of p53, p21/WAF1, Bax, and Bcl-2 and the activity of caspase-3 were measured. FACS analysis was also carried out to determine changes in cell cycle distribution as a response to cisplatin. RESULTS: The four cell lines differed in sensitivity to cisplatin. A2780 was the most sensitive and IGROV-1 was the least sensitive. In contrast, IGROV-1 cells showed the highest percentage of apoptosis (30-40%), while A2780 had the lowest percentage (6-14%) (r = 0.99). The occurrence of apoptosis was not dependent on functional p53. Of interest, caspase-3 activity was in line with the percentage of apoptosis and preceded DNA fragmentation and the visualization of condensed nuclei. Wild-type p53 cells accumulated in the S phase, while OVCAR-3 arrested in the G2/M phase. The protein expression levels of p53, p21/WAF1, Bax, and Bcl-2 varied in time, but were not related to the apoptotic behavior of the cells. Upregulation of p53 was already evident before activation of caspase-3. CONCLUSIONS: Time-dependent changes in the various factors involved in the apoptotic process induced by equitoxic doses of cisplatin vary strongly among the cell lines. Caspase-3 activation plays an important role in cisplatin-induced apoptosis and this precedes morphological changes. The ability of cells to enter apoptosis, however, does not seem to predict sensitivity to cisplatin.

Antineoplastic Agents↗
PubMed2002

BNP7787, a novel protector against platinum-related toxicities, does not affect the efficacy of cisplatin or carboplatin in human tumour xenografts.

BNP7787 (2',2'-dithio-bis-ethane sulphonate sodium), a water-soluble disulphide, is chemically and mechanistically different from other sulphur-containing chemoprotective agents. Presently, BNP7787 is under investigation for its protective properties with regard to the side-effects of platinum compounds. In this study, we evaluated BNP7787, mesna and amifostine for their effects on the antitumour activity of platinum compounds. Continuous exposure to BNP7787 did not affect the antiproliferative effects of cisplatin or carboplatin, but the efficacy of both compounds was reduced in the presence of mesna in vitro in two human ovarian cancer cell lines. BNP7787 or amifostine combined with cisplatin or carboplatin given in standard schedules for the treatment of nude mice bearing well-established OVCAR-3 xenografts did not interfere with platinum-induced inhibition of tumour growth. Of interest, BNP7787 or amifostine co-administered with carboplatin was significantly more effective than carboplatin alone (P<0.01). In the presence of amifostine, doses of cisplatin and carboplatin could be safely increased by factors of 1.6 and 1.5, respectively. Unlike in a previous study of BNP7787 in tumour-bearing rats, BNP7787 did not protect against additional weight loss following treatment with higher doses of cisplatin in OVCAR-3-bearing mice. Pharmacokinetics of (mixed) disulphides including BNP7787 and extractable mesna in deproteinised plasma revealed a rapid disappearance of BNP7787 and an AUC(5-60) value of mesna 9-fold lower than that calculated after an equivalent dose of mesna by weight. We can conclude that BNP7787 does not interfere with the antitumour activity of platinum compounds in vitro and in vivo. Clinical trials are underway to evaluate the protection of normal tissues by BNP7787 when combined with cisplatin.

Amifostine↗
PubMed2001

Induction of vascular endothelial growth factor expression and hypoxia-inducible factor 1alpha protein by the oxidative stressor arsenite.

Recent evidence suggests that vascular endothelial growth factor (VEGF) expression is up-regulated by oxidative stressors through activation of hypoxia-inducible Factor 1 (HIF-1). To investigate whether this is a general phenomenon, we studied the effects of the sulfhydryl reagent arsenite on VEGF expression in human ovarian cancer cells. Arsenite potently induces the production of reactive oxygen species (ROS) in several cell systems and directly interacts with sulfhydryl groups of cellular thiols. We report that arsenite induces VEGF mRNA and protein levels in normoxic H134 and OVCAR-3 cells. Arsenite also increases HIF-1alpha protein levels, suggesting a role for HIF-1 in the induction of VEGF expression. Pretreatment with the ROS inhibitors catalase and mannitol attenuated arsenite-induced ROS production, but did not affect induction of VEGF mRNA and HIF-1alpha protein. In contrast, pretreatment with the thiol antioxidants glutathione or N-acetylcysteine completely abrogated both effects, whereas a potentiation was observed by depletion of intracellular glutathione. These results demonstrate that arsenite-induced VEGF mRNA and HIF-1alpha protein expression is independent of increased ROS production but critically regulated by the cellular reduced glutathione content. In addition, these data suggest the involvement of a thiol-sensitive mechanism in the regulation of VEGF mRNA expression and HIF-1alpha protein in human ovarian cancer cells.

Arsenites↗
PubMed2001

Pronounced antitumor efficacy of doxorubicin when given as the prodrug DOX-GA3 in combination with a monoclonal antibody beta-glucuronidase conjugate.

A glucuronide doxorubicin prodrug N-[4-doxorubicin-N-carbonyl (oxymethyl) phenyl] O-beta-glucuronyl carbamate (DOX-GA3) has been developed to improve the antitumor effects of doxorubicin (DOX). The prodrug was originally designed to be activated into drug by human beta-glucuronidase (GUS) released from tumor cells in necrotic areas of tumor lesions. The aim of this study was to further improve the antitumor effects of DOX-GA3 by means of antibody-directed enzyme prodrug therapy (ADEPT). We thus investigated if the administration of an enzyme-immunoconjugate prepared from the pancarcinoma Ep-CAM specific monoclonal antibody (MAb) 323/A3 and beta-glucuronidase would result in improved antitumor effects because of additional enzyme localization in tumor tissue. In vitro, the prodrug DOX-GA3 was found to be 12-times less toxic than the parent drug DOX in a human ovarian cancer cell line. Immunospecific and complete activation of the prodrug took place when the cells were pretreated with 323/A3-beta-glucuronidase conjugate. In nude mice bearing s.c. human ovarian cancer xenografts (FMa) the maximum tolerated dose (MTD) of DOX-GA3 (500 mg/kg weekly x 2) was much higher when compared with that of DOX (8 mg/kg weekly x 2). In mice bearing well-established FMa xenografts, the standard treatment of DOX at the MTD (8 mg/kg weekly x 2) resulted in a tumor growth inhibition of 67%. Treatment with DOX-GA3 at a single dose of 500 mg/kg resulted in a better tumor growth inhibition of 87%. The combination of DOX-GA3 (500 mg/kg) with 323/A3-mGUS conjugate and anti-GUS MAb 105, to clear circulating conjugate, improved the antitumor effect even further to 98%. At the lower dose of 250 mg/kg DOX-GA3 tumor growth inhibition (34%) was not better than that of DOX. The combination, however, of DOX-GA3 at 250 mg/kg and 323/A3-mGUS conjugate plus MAb 105 again greatly improved the antitumor effect (growth inhibition of 93%). DOX given at 8 mg/kg weekly x 2 did not result in tumor regressions. As a result of ADEPT, the number of regressions of tumors improved from 0 out of 12 to 9 out of 11 at a dose of 250 mg/kg DOX-GA3. At the higher prodrug dose (500 mg/kg) the number of regressions improved from 2 out of 12 to 9 out of 10 as a result from the addition of enzyme-immunoconjugate. Our studies show that the efficacy of the widely used anti-cancer agent DOX may be improved by using the prodrug DOX-GA3, in combination with the tumor-specific enzyme-immunoconjugate 323/A3-mGUS and a conjugate clearing antibody.

Animals↗
PubMed2001

A novel doxorubicin-glucuronide prodrug DOX-GA3 for tumour-selective chemotherapy: distribution and efficacy in experimental human ovarian cancer.

The doxorubicin (DOX) prodrug N-[4-doxorubicin-N-carbonyl (oxymethyl) phenyl] O-beta-glucuronyl carbamate (DOX-GA3) was synthesised for specific activation by human beta-glucuronidase, which is released in necrotic areas of tumour lesions. This novel prodrug was completely activated to the parent drug by human beta-glucuronidase with V(max)= 25.0 micromol x min(-1) x mg(-1) and K(m) = 1100 microM. The pharmacokinetics and distribution of DOX-GA3 in nude mice bearing human ovarian cancer xenografts (OVCAR-3) were determined and compared with DOX. Administration of DOX at 8 mg x kg(-1) i.v. (maximum tolerated dose, MTD) to OVCAR-3-bearing mice resulted in a peak plasma concentration of the drug of 16.4 microM (t = 1 min). A 7.6-times lower peak plasma concentration of DOX was measured after injection of DOX-GA3 at 250 mg x kg(-1) i.v. (50% of MTD). In normal tissues the prodrug showed peak DOX concentrations that were up to 5-fold (heart) lower than those found after DOX administration. DOX-GA3 activation by beta-glucuronidase in the tumour yielded an almost 5-fold higher DOX peak concentration of 9.57 nmol x g(-1) (P< 0.05) than the peak concentration of only 2.14 nmol x g(-1) observed after DOX. As a consequence, the area under the curve of DOX calculated in tumour tissue after DOX-GA3 (13.1 micromol x min(-1) x g(-1)) was 10-fold higher than after DOX (1.31 micromol x min(-1) x g(-1)). The anti-tumour effects of DOX-GA3 and DOX were compared at equitoxic doses in OVCAR-3 xenografts at a mean tumour size of 125 mm(3). The prodrug given i.v. at 500 mg x kg(-1) weekly x 2 resulted in a maximum tumour growth inhibition of 87%, while the standard treatment with DOX at a dose of 8 mg x kg(-1) i.v. weekly x 2 resulted in a maximum tumour growth inhibition of only 56%. Treatment with DOX-GA3 was also given to mice with larger tumours containing more necrosis. For tumours with a mean size of 400 mm(3) the specific growth delay by DOX-GA3 increased from 2.7 to 3.9. Our data indicate that DOX-GA3 is more effective than DOX and suggest that the prodrug will be specifically advantageous for treatment of advanced disease.

Animals↗
PubMed2001

Frederine, a new and promising protector against doxorubicin-induced cardiotoxicity.

The flavonoid 7-monohydroxyethylrutoside (monoHER) can protect against doxorubicin-induced cardiotoxicity. A drawback of monoHER therapy would be the relatively high dose needed to obtain complete protection (500 mg/kg in mice). Therefore, we synthesized a series of new compounds with improved antioxidant properties. After characterization of antioxidant activity, cardioprotection in vitro, and possible toxic properties in hepatocytes, we selected Frederine for additional investigations in vivo. In the present study, it was found that this compound did not induce weight loss or (gross) organ changes in mice in a treatment schedule of 170 mg/kg i.p., 5 times/week during 2 weeks. We recorded the electrocardiogram telemetrically in mice during and 2 weeks after the combined treatment with doxorubicin (4 mg/kg, i.v.) and 5 times Frederine (68 mg/kg, i.p.; equimolar to 100 mg/kg monoHER) for 6 weeks. Complete protection against doxorubicin-induced cardiotoxicity was found, indicating that Frederine is at least 5 times more potent than monoHER. Frederine did not have a negative influence on the antiproliferative effects of doxorubicin on A2780, OVCAR-3, and MCF-7 cells in vitro and on OVCAR-3 xenografts grown in nude mice when administered 5 min before doxorubicin (8 mg/kg i.v.) and 4 days thereafter with an interval of 24 h. It can be concluded that we succeeded in designing a better cardioprotector than monoHER. Therefore, Frederine merits further investigation as a possible protector against doxorubicin-induced cardiotoxicity in cancer patients.

Analysis of Variance↗
PubMed2001

92nd AACR. Anti-angiogenic agents.

This year's meeting covered a vast number of subjects of which a few warrant specific discussion due to current interest. Research activities are expanding in the potential use of anti-angiogenic and antivascular targeting agents for treatment of cancer. Studies on the mechanisms of action of this wide variety of agents remain the focus of attention. A large series of abstracts was dedicated to apoptosis and approaches to stimulate tumor cells to enter the apoptotic death pathway. Insight into DNA damage and repair is increasing, as well as measures to circumvent cellular drug resistance. Another subject to mention is the generation of dendritic cells for immunotherapy. And last, but not least, presentations concerning the state-of-the-art of microarray technology not only included encouraging data, but also reviewed the problems encountered when using patient's tumor samples for analysis.

Journal Article↗