scholarly journals Further Studies on Cytostatic Activity of Alkoxymethyl Purine and Pyrimidine Acyclonucleosides

1999 ◽  
Vol 54 (11) ◽  
pp. 923-931
Author(s):  
Hanna Modrzejewska ◽  
Marcin Dramiński ◽  
Anna Zgit-Wróblewska ◽  
Janusz Greger
Keyword(s):  
Tumor Growth ◽  
Dna Polymerase ◽  
Amelanotic Melanoma ◽  
Cytostatic Activity ◽  
Tumor Mass ◽  
Reduce Tumor Growth ◽  
Inhibition Of Tumor Growth ◽  
Derivatives Of ◽  
Tumor Dna

The influence of 14 acyclonucleosides1, derivatives of adenine, guanine, uracil and thymine on the phosphorylation of dAdo, dGuo, dCyd and dThd occurring in the cytosol of growing amelanotic melanoma transplanted to Syrian hamsters, as well as on inhibition of tumor growth were studied. From among the studied ACNs eight were tested earlier (Modrzejewska et al., 1996, The influence of alkoxymethyl purine and pyrimidine acyclonucleosides on growth inhibition of Kirkman-Robbins hepatoma and possible mechanism of their cytostatic activity, Z. Naturforch. 51c, 75 - 80 ) ; from among the newly synthesized ACNs, 1,3-N, N-diallyloxymethylthymine (AMT2), 1-N-allyloxymethyl-5,6-tetramethyIeneuracil (AMUTM ), and tested previously 1-N-allyloxymethylthymine (AMT1), administered i.p. in a dose of 0.2 mmol /kg body weight reduce the tumor mass from 0.98 g to 0.64 g ± 0.11 g (i.e. 35% ± 12% ). 48 hours after i.p. administration of the mentioned ACNs in the same dose a reduction of tumor mass is accompanied by the inhibition of dAMP, dGMP and dTM P synthesis. AMT1 inhibits dThd phosphorylation from 6.2 to 4.22; AMT2 suppresses dAdo, dGuo and dThd phosphorylation by, correspondingly, from 2.8 to 1.7, from 10.8 to 7.5 and from 6.2 to 4.2; AMUTM depresses dAMP synthesis from 2.8 to 1.6 (all data: μmol of 2’dNMP formed per mg of protein per min. × 10-4 ). None of the 14 studied acyclonucleosides influences dCMP synthesis. In vivo, after hydration of allyloxymethyl group to hydroxypropoxymethyl residue (having -CH2OH group), AMT1, AMT2 and AMUTM undergo phosphorylation to corresponding triphosphates. Phosphorylated ACNs are not incorporated into tumor DNA, however they inhibit dAdo, dGuo and dThd incorporation into DNA. It is concluded that ACN triphosphates are not substrates for DNA polymerase but, competing with dATP dGTP and dTTP, inhibit incorporation of these 2’dNTP into DNA and, in consequence, reduce tumor growth, which is presumed to be the main mechanism of cytostatic activity of the studied ACNs.

Inhibition of tumor growth induced by histamine: In vivo and in vitro studies

1993 ◽  
Vol 38 (3-4) ◽  
pp. C175-C177 ◽  
Author(s):  
G. P. Cricco ◽  
C. A. Davio ◽  
R. M. Bergoc ◽  
E. S. Rivera
Keyword(s):  
Tumor Growth ◽  
In Vitro Studies ◽  
Inhibition Of Tumor Growth

A Novel In Vivo Animal Model for Human Multiple Myeloma Based on Bioluminescence Imaging of Tumor Cell Growth.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3452-3452
Author(s):  
Anton C. Martens ◽  
Henk Rozemuller ◽  
Ellen van der Spek ◽  
Lijnie Bogers-Boer ◽  
Niels van de Donk ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Tumor Growth ◽  
Quantitative Evaluation ◽  
Bioluminescence Imaging ◽  
Growth Curves ◽  
Population Doubling ◽  
Tumor Mass ◽  
In Vivo Animal Model

Abstract Preclinical testing of new therapeutical strategies for the treatment of multiple myeloma (MM) requires animal models that closely resemble human disease and allow quantitative evaluation of the applied therapy. Models that meet both requirements have thus far not been described. Here we present a novel in vivo MM model by engraftment of MM U266 or RPMI-8226/S cells, both of human origin, into RAG2γc double knock-out mice. These mice are totally immune deficient because they lack T-, B and NK cells and the mice easily accept human cells (van Rijn et al., Blood 2003, Rozemuller et al., 2004). After intravenous injection of 2x106 MM cells engraftment and outgrowth occurred in all mice but was limited to the bone marrow compartment only. Flow cytometry (FCM) confirmed the presence of human CD45/38/138 positive MM cells in femur, spine, tibia and sternum bone specimens. Infiltration into other organs was not observed. In a next step MM cells were stably transduced using a retroviral vector encoding both the Green Fluorescent Protein (GFP) and firefly Luciferase (fLuc) marker genes. Technical advances in recent years in optical imaging by Bioluminescence Imaging (BLI) techniques allow visualization and quantification of bioluminescent light by detecting photons that are transmitted through mammalian tissue. When luciferase converts the substrate luciferin, photons are emitted that can be registered by using sensitive CCCD cameras. The absolute number of photons that are produced correlates, in our application, with local tumor mass. Mice were injected i.v. with 2x106 GFP-fLuc transduced MM cells (U266 or RPMI8226/S) and imaged weekly using BLI. Within 2 weeks after injection significant BLI signals were detectable. Per mouse 5-10 foci showed luciferase activity, predominantly in the pelvic region, skull, limbs, sternum, ribs and the spine. This low frequency of engraftment is in line with earlier reports on RPMI8226/S (Mitsiades et al., Cancer Res 2003). At 9 weeks the first mice developed hind leg paralysis which could be attributed to tumor associated spinal lesions. After 12 weeks the last mouse was sacrificed. BLI revealed that the intensity of light production at the various sites of tumor growth within individual mice as well as between mice showed a similar increase. This reflects an increase in tumor mass. Quantitative analysis of subsequent BLI images allowed construction of tumor growth curves of the total tumor mass per mouse as well as for the individual foci of MM growth in individual mice. We typically observed exponential growth, with growth curves running parallel with an average population doubling time of approximately 4–5 days. The range in which tumor growth could be monitored (and as a consequence also the response to treatment) spans 3–4 decades. In contrast with previously reported murine models for human MM where -next to bone marrow homing- also extra-skeletal tumors were observed our model almost exclusively shows homing of MM cells to the BM and is therefore more consistent with the clinical manifestation in myeloma patients. The major advantage of the model is the option for quantitative evaluation of the effect of a given treatment on the tumorload. Currently we are studying the efficacy of newly developed geranyl-geranyl-transferase inhibitors (GGTI). In conclusion, we have developed a novel in vivo model to study the characteristics of homing and outgrowth of MM and for quantitative evaluation of the efficacy of the therapeutic intervention applied.

A preclinical survey on the efficacy of NSC-290205 in combination with doxorubicin (ADR) in Lewis lung carcinoma (LLC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17131-17131
Author(s):  
A. Papageorgiou ◽  
E. Stergiou ◽  
I. Boukovinas ◽  
G. Geromichalos ◽  
I. Stergiou
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Maximum Effect ◽  
Base Pairs ◽  
Chop Regimen ◽  
C57bl Mice ◽  
Inhibition Of Tumor Growth ◽  
Reduced Toxicity ◽  
The Right ◽  
Derivatives Of

17131 Background: NSC-290205 (A) is a hybrid synthetic antitumor ester, which combines a D-lactam derivative of androsterone and nitrogen mustard. Studies on modified steroidal esters of carboxylic derivatives of N,N-bis(2-chloroethyl)aniline, have shown that they exhibit reduced toxicity and increased antitumor activity and specificity. In this study we investigated the antitumor activity of compound A in combination with ADR (AHOP) in comparison with standard CHOP regimen. Methods: C57Bl mice were used for the antitumor evaluation of AHOP/CHOP. Experiments were initiated by implanting the tumor. LLC cells (purchased by NCI, Bethesda, USA) were implanted intramuscularly into the right hind leg as a suspension of 7 × 106 cells in 0.1 ml. The antitumor activity was assessed from the inhibition of tumor growth by volume in cm3 and the oncostatic parameter T/C % according to the protocol of experimental evaluation of antitumor drugs of the NCI, USA. Treatments were given as a single dose (D) on day 1, intermitted dose (D/2 × 3) on days 1, 5, 9 or consecutive dose (D/4 × 9) on days 1 through 9. Results: Treatment with A or cyclophosphamide produced almost equal borderline activity. Moreover, both CHOP and AHOP regimens showed significant and comparable antitumor effect (p < 0.05 by the Wilkoxon test). AHOP caused the maximum effect inhibiting the tumor growth by 67.7% and T/C values of 270%. CHOP was less effective producing 54.8% tumor inhibition and T/C values of 238%. Conclusions: It is very likely that the D-lactamic steroid (androstan) alkylator for A, containing the -NHCO group, combined with ADR, which intercalates between base-pairs, is the explanation for higher activity of AHOP vs. CHOP. This significant effect of NSC-290205 with the anthracycline adriamycin on LLC adds to NSC-290205 advantage for further clinical development. No significant financial relationships to disclose.

The mechanism of low molecular weight heparin (LMWH) inhibition of tumor growth

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13093-13093 ◽  
Author(s):  
S. L. Smiley ◽  
D. O. Henry ◽  
M. K. Wong
Keyword(s):  
Endothelial Cells ◽  
Tumor Growth ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Receptor System ◽  
Fgf Receptor ◽  
Tumor Inhibition ◽  
Inhibition Of Tumor Growth

13093 Background: Clinical studies show that LMWHs improve survival in cancer patients. There is compelling and mounting evidence that non-anticoagulation factors are at play, and that these may be contributing in a major way to improved patient outcome. Methods and Results: Dalteparin, enoxaparin, and tinzaparin were tested for their in vivo ability to inhibit tumor lines engineered for aggressive angiogenesis-driven growth. Therapeutic daily doses of drug administered the day following tumor inoculation resulted in significant angiogenesis and tumor inhibition. We previously showed that LMWHs inhibit fibroblast growth factor (FGF) -induced mitogenesis of Tumor Derived Endothelial Cells (TDECs) in a time and concentration dependent manner in vitro. We now show that this endothelial inhibition occurs through LMWHs-mediated reduction of phosphorylation and down stream signaling through ERK. The potency of LMWH was significantly reduced when TDECs were pretreated with heparinase- suggesting that the molecular target for LMWH may be the cell surface, low affinity FGF receptor system. Both our in vivo and in vitro studies demonstrate that angiogenesis and tumor inhibition are greatest for dalteparin > tinzaparin > enoxaparin. Clues to the heparin-TDECs interaction comes from tracking the real-time movement of FGF using a highly fluorescent nanocrystal bead decorated on its surface with FGF. High resolution video-microscopy shows FGF binding onto TDEC surfaces, but once heparin enters the environment, FGF detaches from the TDECs and migrates to the heparin. This ultimately results in significant TDEC growth inhibition as compared to controls. Conclusion: LMWH treatment at pharmacologic doses significantly blunts tumor growth and angiogenesis. This inhibition resides in part via heparin’s ability to sequester FGF from the low affinity receptor system on tumor endothelial cells. No significant financial relationships to disclose.

Inhibition of tumor growth in vitro and in vivo by a monoclonal antibody against human chorionic gonadotropin β

2007 ◽  
Vol 114 (2) ◽  
pp. 94-102 ◽  
Author(s):  
Ning Yu ◽  
Wei Xu ◽  
Zhenggang Jiang ◽  
Qinghua Cao ◽  
Yiwei Chu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tumor Growth ◽  
Chorionic Gonadotropin ◽  
Human Chorionic Gonadotropin ◽  
Inhibition Of Tumor Growth

scholarly journals Inhibition of tumor growth in vivo by a nanoparticle-based therapeutic cancer vaccine targeting HAAH

2013 ◽  
Vol 1 (Suppl 1) ◽  
pp. P269
Author(s):  
Steven Fuller ◽  
Solomon Stewart ◽  
Michael Lebowitz ◽  
Kanam Malhotra ◽  
Hossein Ghanbari
Keyword(s):  
Tumor Growth ◽  
Cancer Vaccine ◽  
Therapeutic Cancer Vaccine ◽  
Inhibition Of Tumor Growth

MAb 14C5 against a human cell substrate adhesion molecule for inhibition of tumor growth in-vivo

1997 ◽  
Vol 33 ◽  
pp. S42
Author(s):  
P. Giffels ◽  
S. Köhler ◽  
Ch. DePotter ◽  
E. Coene ◽  
D. Nagel ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Adhesion Molecule ◽  
Human Cell ◽  
Substrate Adhesion ◽  
Cell Substrate ◽  
Inhibition Of Tumor Growth ◽  
Cell Substrate Adhesion

scholarly journals OR06-02 TBR-760, a Chimeric Somatostatin-Dopamine Compound, Arrests Aggressive Non-Functioning Pituitary Adenoma Growth In Vivo

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Heather A Halem ◽  
Ute Hochgeschwender ◽  
Arunthi Thiagalingam ◽  
Michael D Culler
Keyword(s):  
Mouse Model ◽  
Tumor Growth ◽  
Pituitary Adenomas ◽  
Initial Study ◽  
Mouse Tumors ◽  
Inhibition Of Tumor Growth ◽  
Null Mutant Mice ◽  
The Individual

Abstract TBR-760 is a chimeric dopamine (DA)-somatostatin (SST) compound with potent agonist activity at both DA type 2 (D2R; EC50 0.064nM) and SST type 2 (SSTR2; EC50 1.2nM) receptors. Prior studies have demonstrated that the chimeric DA-SST compounds are more potent and effective than either individual or combinations of individual DA and/or SST analogs in inhibiting secretion from pituitary adenomas. Non-functioning pituitary adenomas (NFPA) express high levels of D2R as well as lower levels of SSTRs, including the type 2 receptor (1), and thus have an appropriate receptor profile to respond to TBR-760. The present study examines the ability of TBR-760 to inhibit tumor growth in a mouse model of aggressive NFPA. Heterozygous and null mutant mice lacking one or both copies, respectively, of the pro-opiomelanocortin (POMC) gene (POMC-KO mice)(2) spontaneously develop aggressive, non-secreting pituitary adenomas (3). The POMC-KO mouse tumors have been shown to express D2R and SSTR2 at a similar level as human NFPAs (4). In addition, merging of microarray data (Affymetrix, U133 plus_2.0 and Mouse Genome 430 2.0 arrays), reveals 154 common gene signatures between human NFPAs and the POMC-KO mouse tumors. In an initial study, heterozygous POMC-KO mice with an established pituitary tumor of approx. 10mm3 (mean volume 8.9±0.3), as determined by MRI, were treated with a range of TBR-760 doses (0.125 to 12.5mg/kg, sc, QD) for 60 days. During that time, tumors in vehicle-treated mice increased in size by 890±0.7%, whereas all doses of TBR-760 tested resulted in a nearly complete inhibition of tumor growth from treatment initiation. We then compared the effect of the TBR-760 chimera with that of its individual SST agonist (SSTA) and DA agonist (DAA) components on tumor growth in the POMC-KO mice. As in the earlier study, TBR-760 treatment (1mg/kg, sc, QD), initiated when the mice had an established tumor of approx. 10mm3, completely arrested tumor growth during the 8 weeks of treatment (final mean tumor volume of 8.5±1.3mm3 vs. 54.61±10.6mm3 in vehicle-treated mice). Treatment with equimolar or 10x-higher doses of the individual SSTA or DAA, either alone or in combination, had no significant effect on tumor growth, except in the lower dose DAA group where a modest suppression of tumor growth was observed. These data demonstrate that only the dual DA-SST chimeric compound, TBR-760, completely arrested tumor growth in the POMC-KO mouse model of NFPA. Further, despite the highly aggressive nature of the POMC-KO tumors, significant tumor shrinkage was observed in 20% of the mice treated with TBR-760. These results support the development of TBR-760 as a medical therapy to prevent or arrest the growth of NFPAs and, potentially, to induce NFPA shrinkage. References: (1) Florio et al., 2008 Endocr Relat Cancer; 15: 583-596. (2) Yaswen et al., 1999 Nat Med; 9:1066-70 (3) Karpac J et al., 2006 Cell Mol Biol; 52: 47-52.

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