Indoleamine 2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan 2,3-dioxygenase (TDO) represent some of the key immune regulators. Their increased activity has been demonstrated in a number of human malignancies but not yet in chronic myeloid leukemia (CML). In the present study, the activity of these enzymes was tested in 29 CML patients and 28 healthy subjects by monitoring the kynurenine (KYN)/tryptophan ratio. Serum samples taken prior to the therapy displayed a highly significant difference in KYN levels between the patient and control groups. However, increased KYN levels were detected in only 13 (44.8%) of these CML patients. The KYN levels in pretreatment sera of the patients correlated with the tumor burden. There was also a strong correlation between KYN levels and uric acid levels (UA). This suggests but does not prove the possible involvement of UA in activating IDO family of enzymes. Whenever tested, the increased KYN levels normalized in the course of the therapy. Patients with normal KYN levels in their pretreatment sera and subsequently treated with interferon-α, showed a transitory increase in their KYN levels. The present data indicate that CML should be added to the malignancies with an increased activity of the IDO family of enzymes and suggest that IDO inhibitors may be used in the treatment of CML patients.
- MeSH
- biologické markery krev MeSH
- chronická myeloidní leukemie * MeSH
- dospělí MeSH
- indolamin-2,3,-dioxygenasa MeSH
- kynurenin * krev MeSH
- kyselina močová * MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- tryptofan * krev MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
Stromal-derived factor 1α (SDF‑1α, also known as CXCL12) is a chemokine that exerts its effects through the G-protein coupled receptors, C-X-C chemokine receptor type 4 (CXCR4) and 7 (CXCR7). There is marked evidence that the SDF-1/CXCR4 axis is involved in the pathogenesis of leukemia and therapies that target this axis are under development. The present study aimed to increase the efficacy of a DNA-based bcr-abl vaccine by simultaneously immunizing mice with a plasmid carrying the whole SDF-1α gene. Bcr-abl‑transformed 12B1 cells were used to challenge the mice. These cells have the oncogenic potential to induce both leukemia following intravenous inoculation and lymphoma-type solid tumors after subcutaneous inoculation. Administering an SDF‑1 carrying plasmid together with the bcr-abl vaccine resulted in increased survival following a challenge with subcutaneously administered 12B1 cells, although the difference was not statistically significant. However, there was a difference when the animals that developed subcutaneous tumors were only taken into consideration. In doubly-treated mice, significantly more mice failed to develop solid tumors than mice that had only received the bcr-abl vaccine. By contrast, the occurrence of fatal leukemia was significantly higher in the mice that were treated with the SDF-1 plasmid, regardless of whether they were immunized with the bcr-abl-vaccine. No humoral or cellular immune responses against SDF‑1 were detected in the treated mice, which suggested that the changes in oncogenic potential of 12B1 cells were due to the activity of SDF-1 itself.
- MeSH
- bcr-abl fúzové proteiny genetika MeSH
- chemokin CXCL12 genetika metabolismus MeSH
- chronická myeloidní leukemie mortalita terapie veterinární MeSH
- DNA vakcíny imunologie terapeutické užití MeSH
- faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus MeSH
- HEK293 buňky MeSH
- lidé MeSH
- míra přežití MeSH
- molekulární sekvence - údaje MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- plazmidy genetika metabolismus MeSH
- receptory CXCR4 metabolismus MeSH
- sekvence aminokyselin MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We investigated whether a genetic modification of BCR-ABL-transformed mouse cells that resulted in endostatin (ES) production altered their oncogenic potential. Mouse B210 cells, which express p210bcr-abl fusion protein and induce leukemia-like disease and extremely rarely solid tumors after intravenous (i.v.) administration, were used. The cells were transfected with a plasmid carrying genes for mouse ES and resistance to blasticidine. Transduced cells were isolated in media supplemented with blasticidine. Production of ES was determined by Western blotting. For further tests, two clones were selected, and their pathogenicity after i.v. inoculation was tested. Compared with the parental B210 cells, the capability of both gene-modified cell clones to induce lethal leukemia was reduced. However, mice that did not succumb to leukemia subsequently developed solid tumors. They were composed of poorly differentiated cells with irregular nuclei and roughly granular chromatin and were well vascularized. FISH revealed the presence of the BCR-ABL fusion gene both in tumors and spleens. Immunohistological investigation of the tumors demonstrated the production of ES in vivo and the cell lines derived from the tumors produced detectable amounts of ES, this demonstrating that the formation of solid tumors was not associated with the loss or silencing of the ES gene.
- MeSH
- bcr-abl fúzové proteiny genetika metabolismus MeSH
- endostatiny metabolismus farmakologie sekrece MeSH
- endoteliální buňky pupečníkové žíly (lidské) účinky léků fyziologie MeSH
- histokompatibilita - antigeny třídy I metabolismus MeSH
- Kaplanův-Meierův odhad MeSH
- kultivační média speciální farmakologie MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- nádorová transformace buněk MeSH
- proliferace buněk MeSH
- transformované buněčné linie metabolismus patologie transplantace MeSH
- transplantace nádorů MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- financování organizované MeSH
- Publikační typ
- abstrakty MeSH
- MeSH
- financování organizované MeSH
- Publikační typ
- abstrakty MeSH
- MeSH
- aplikace inhalační MeSH
- aplikace orální MeSH
- hematoencefalická bariéra * MeSH
- játra patologie MeSH
- kadmium * škodlivé účinky toxicita MeSH
- klinické laboratorní techniky MeSH
- ledviny patologie MeSH
- mozek patologie MeSH
- potkani Wistar MeSH
- pracovní expozice * MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
