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Written by Anti-Cancer Drugs
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Tuesday, 17 October 2006 |
RP101 improves the efficacy of chemotherapy in pancreas carcinoma cell lines and pancreatic cancer patients.
(Source: Anticancer Drugs.) Full Citation:Anticancer Drugs. 2006 Oct;17(9):1045-1056.
Publisher's Abstract
Fahrig R, Quietzsch D, Heinrich JC, Heinemann V, Boeck S, Schmid RM, Praha C, Liebert A, Sonntag D, Krupitza G, Hanel M.
RESprotect, Dresden Clinics for Internal Medicine II Clinics for
Internal Medicine III Institute for Laboratory Medicine, Klinikum
Chemnitz GmbH, Kuchwald
University Munich, Klinikum Grosshadern Technical University Munich,
Klinikum Rechts der Isar, Germany Institute for Clinical Pathology,
University Vienna,
Vienna, Austria.
RP101 [(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU)], which supports
apoptosis and prevents the acquisition of chemoresistance, was tested
in cultured human ancreatic tumor cells. RP101 downregulated uridine
phosphorylase, a marker of poor prognosis, and APEX1, which is involved
in DNA repair, and repressed Stat3 and its target vascular endothelial
growth factor. Furthermore, RP101 activated antitumor immunity as
demonstrated by enhanced cytolytic activity of NK-92 Natural killer
cells. This was concomitant with an enhanced expression of lymphotoxins
alpha and beta, natural killer cell transcript 4, tumor necrosis factor
LIGHT/TNFSF-14, and intercellular adhesion molecule-1 in pancreas
carcinoma cells. These results encouraged us to investigate the effect
of RP101 in pancreas cancer patients. Here, we present data from two
RP101 combination therapy schemes. In a first pilot study, 13 patients
in stage III and VI of the disease were treated with gemcitabine
+cisplatin+RP101. RP101 co-treatment enhanced remissions, survival and
time to progression. Seventy-seven percent of the patients lived or
have lived longer than 1 year, and 23% have lived more than 2 years.
Median survival was 447 days, time to progression 280 days and the
response rate 33%. A second study with 21 patients in similar stages of
disease, treated with RP101+gemcitabine alone, confirmed the results of
the pilot study. Eighty-three percent of the presently evaluable
patients live or lived 0.5 years or longer and 33% 1 year or longer.
Considering both studies, the tumor control was 94%. The data indicate
that acquisition of chemoresistance was prevented and the antitumor
efficacy of standard chemotherapy was improved. To our knowledge, RP101
co-treatment is more efficient than any other regimen published.
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Written by Journal of Clinical Oncology
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Tuesday, 20 June 2006 |
ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 14000
R. Fahrig, D. Quietzsch, V. Heinemann, A. Liebert, M. Haenel
Background: (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU, RP101), which supports apoptosis and prevents the acquisition of chemoresistance, was tested in cultured human pancreatic tumor cells. RP101 down-regulated uridine phosphorylase, a marker of poor prognosis, and APEX1, which is involved in DNA repair, and repressed Stat-3 and its target VEGF. Furthermore, RP101 activated antitumor immunity. These results encouraged us to investigate the effect of RP101 in combination with gemcitabine (GEM) and cisplatin (CIS) in patients with advanced pancreatic cancer.
Methods: A phase II pilot trial was designed to compare the GEM/CIS/RP101 combination to historical GEM/CIS combination. The primary endpoint was survival. 13 pts with histological documented pancreatic carcinoma received GEM 1.000 mg/m2 plus CIS 50 mg/m2 on days 1 and 15 of a 28-day schedule. RP101 treatment was on the same day and for four days after chemotherapy (500 mg/day).
Results: All patients showed at least a stable disease, and 33% of them a PR. As a historical control, 22 pts were selected by random generator from 98 patients enrolled in a previous Phase III study performed in the same centers, 15 with stage IV and 7 with stage III disease, resulting in a similar proportion of stage III to IV patients as in the RP101 co-treatment group (nine stage IV and four stage III). In the RP101-co-treatment group the median survival was significantly longer than that of the historical control group (447 days vs. 186 days, p=0.007). Time to progression (TTP) was also prolonged (280 days vs. 104 days, p=0.004). Ten of the 13 pts lived longer than one year, 4 nearly two years after first treatment.
Conclusions: The combined use of GEM/CIS/RP101 prolonged progression-free and overall survival in locally advanced and metastatic pancreatic cancer when compared to all published studies with all combinations of drugs. A repeat study with GEM/RP101 shows similar promising results indicating that the combination of RP101 with GEM should be explored in larger studies in patients with advance pancreatic cancer.
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Written by Journal of Clinical Oncology
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Tuesday, 20 June 2006 |
ASCO Annual
Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement),
2006
Abstract No: 14075
Citation: Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 4075
Author(s): M. Haenel, D. Quietzsch, V. Heinemann, S. Boeck, R. M. Schmid, A. Liebert, R. Fahrig
Background: (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU, RP101), was initially tested in a phase 1 pilot study in pancreatic cancer. Patients (n=13) received gemcitabine (1000 mg/m2), cisplatin (50 mg/m2) and RP101 (500 mg/day). The median survival was 447 days and the TTP was 280 days. Ten of the 13 pts lived longer than one year, 4 nearly two years. Based on these promising results a phase 2 study was initiated to explore varying doses of RP101 used with a fixed dose of GEM.
Methods: Pts with advanced pancreatic adenocarcinoma were eligible for treatment in this single arm study. 22 pts (16 stage IV and 5 stage III) received GEM 1000 mg/m2 on days 1, 8 and 15 of a 28-day schedule. RP101 treatment, at doses of 500, 625, 750, 875 or 1000 mg/day, was on the same day and for three days after chemotherapy. The mean age was 60 years and 73% of pts were males.
Results: The results are based on interim data from an ongoing study and patients at the 2 highest dose groups are still being treated. All RP101 dose groups were combined for analyses, which included all enrolled pts. The data on the 6-month survival status show that 41% are alive; 23% dead; and 36% followed less than 6 months. The median survival (95% CI) is 7.1 months (5.9, not calculated) and 14/22 pts (64%) are still alive. The 6 month survival rate (95% CI) is 0.69 (0.52, 0.85). This compares very favorably with a large recent randomized trial in which pts who received GEM alone had a median survival (95%CI) of 5.9 months (5.1-6.7). PFS and TTP continue to be assessed in this ongoing trial. There appears to be a dose dependent increase in peak GEM levels as a function of the dose of RP101. To date, adverse events are consistent with those observed with GEM or the underlying disease.
Conclusion: RP101 may improve treatment of advanced pancreatic cancer when used with gemcitabine. Updated data on survival, PFS, and safety will be presented based on available data.
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Written by Journal of Clinical Cancer Research
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Friday, 21 November 2003 |
AACR-NCI-EORTC International
Conference November 17-21st, 2003 - Development of efficient drugs for the treatment of the “polygenic” phenomenon of chemoresistance
Rudolf Fahrig1, Jörg-Christian Heinrich1, Christian Praha1, Falk Wilfert1, Georg Krupitza2, Denise Sonntag1, Detlef Quietzsch3, Mathias Hänel3
1RESprotect GmbH, Dresden/Germany, 2Institute of Clinical Pathology, University of Vienna/Austria, 3Klinikum Chemnitz Hospital, Department of Hematology, Oncology, Chemnitz /Germany.
Currently, the mechanistic approach of genomics relies on "monogenic" targets. A validated target is usually gene or gene product, which is either over-expressed or over-activated in a disease tissue. Enzyme inhibitors or receptor antagonists may suppress this improper activation, thus reducing the symptoms of a disease. However, most diseases are not caused by a "monogenic" disorder, instead, multiple genes contribute to the pathophysiology. Therefore, disease usually have a "polygenic" background. To treat a "polygenic" phenomenon like chemoresistance, it is necessary to control multiple genes and their products simultaneously. Chemogenomics, the approach of RESprotect, bases on the application of small synthetic molecules, which elicit favourable phenotypic changes. The combination with genomic tools focussing on specific biological pathways qualifies us to understand th broader effect of a drug. That way, it is possible to discover drugs that treat the cause of a disease rather than its symptoms. Reasons for the suppression of cytostatic drug-induced apoptosis are overexpression of oncogenes like DDX1, STAT3, JUN-D, DNA repair genes like APEX, UBE2N, and other survival pathways, but down-regulation of DT-diaphorase and caspases. RP101 antagonized these effects induced by cytostatic drug treatment. Beyond that, during recovery, when treatment was continued with RP101 only, microfilamental proteins were upregulated, proteins involved in ATP generation or cell survival were downregulated. That way, the anti-tumor efficiency of chemotherapy was optimized, and toxic side effects were reduced.
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Written by Cancer Research
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Monday, 15 September 2003 |
Inhibition of Induced Chemoresistance by Cotreatment with (E)-5-(2-Bromovinyl)-2'-Deoxyuridine (RP101)
Rudolf Fahrig,
Jörg-Christian Heinrich,
Bernd Nickel,
Falk Wilfert,
Christina Leisser,
Georg Krupitza,
Christian Praha,
Denise Sonntag,
Beate Fiedler,
Harry Scherthan and
Heinrich Ernst
RESprotect, Dresden, Germany D-01307 [R. F., J-C. H., F. W., C. P., D.
S.]; Baxter Oncology, Frankfurt am Main, Germany 60314 [B. N.];
Institute of Clinical Pathology, University of Vienna, Vienna, Austria
1097 [C. L., G. K.]; Medical School Hannover, Hannover, Germany 30625
[B. F.]; Max-Planck-Institute for Molecular Genetics, Berlin, Germany
14195 [H. S.]; and Fraunhofer Institute for Toxicology and Experimental
Medicine, Hannover, Germany 30625 [H. E.]
Abstract
Induced chemoresistance leads to the reduction of apoptotic responses. Although several drugs are in development that circumvent or decrease existing chemoresistance, none has the potential to prevent or reduce its induction. Here, we present data from a drug that could perhaps fill this gap. Cotreatment of chemotherapy with (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU, RP101) prevented the decrease of apoptotic effects during the course of chemotherapy and reduced nonspecific toxicity. Amplification of chemoresistance genes (Mdr1 and Dhfr) and overexpression of gene products involved in proliferation (DDX1) or DNA repair (UBE2N and APEX) were inhibited, whereas activity of NAD(P)H: quinone oxidoreductase 1 (NQO1) was enhanced. During recovery, when treatment was with BVDU only, microfilamental proteins were up-regulated, and proteins involved in ATP generation or cell survival (STAT3 and JUN-D) were down-regulated. That way, in three different rat tumor models, the antitumor efficiency of chemotherapy was optimized, and toxic side effects were reduced. Because of these beneficial properties of BVDU, a clinical pilot Phase I/II study with five human tumor entities has been started at the University of Dresden (Dresden, Germany). So far, no unwanted side effects have been observed.
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