BACKGROUND AND PURPOSE: Cyclin-dependent kinase 5 (CDK5) has recently emerged as an attractive target in several tumour entities. Inhibition of CDK5 has been shown to have anti-angiogenic effects in vitro and in vivo. However, potent inhibitors of CDK5, which can be applied in vivo, are still scarce. We have recently developed a new series of 5-substituted 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidines that show a preference for inhibiting CDK5 and tested them in vitro and in vivo in a murine model of hepatocellular carcinoma. EXPERIMENTAL APPROACH: All compounds were initially examined for effects on proliferation of HUVECs. The most potent compounds were then tested on migration, and one of them, LGR2674, was selected for assessing effects on nuclear fragmentation, cell cycle, cell viability and metabolic activity. Furthermore, LGR2674 was tested in a tube formation assay and in vivo in a murine model of hepatocellular carcinoma, induced by s.c. injection of HUH7 cells (measurement of in vivo toxicity, tumour vascularization, tumour cell proliferation and tumour size). KEY RESULTS: LGR2674 showed an EC50 in the low nanomolar range in the proliferation and migration assays. Cytotoxic effects started at 50 nM, a concentration that did not influence the cell cycle. In vivo, LGR2674 was well tolerated and caused a clear reduction in vessel density in the tumours; also tumour cell proliferation was inhibited and tumour growth retarded. CONCLUSIONS AND IMPLICATIONS: Pyrazolo[4,3-d]pyrimidine is a novel scaffold for the development of potent CDK inhibitors with in vivo potential. Such structures are good candidates for broadening our pharmacological arsenal against various tumours.

• MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• cyklin-dependentní kinasa 5 antagonisté a inhibitory   MeSH
• experimentální nádory jater farmakoterapie   patologie   MeSH
• inhibitory angiogeneze chemická syntéza   chemie   farmakologie   MeSH
• kultivované buňky MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• myši MeSH
• pohyb buněk účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• pyrazoly chemická syntéza   chemie   farmakologie   MeSH
• pyrimidiny chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• analýza přežití MeSH
• experimentální nádory jater farmakoterapie   chirurgie   MeSH
• kolorektální nádory komplikace   MeSH
• kongresy jako téma MeSH
• lidé MeSH
• metastázy nádorů diagnóza   terapie   MeSH
• monoklonální protilátky terapeutické užití   MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• vaskulární endoteliální růstový faktor A antagonisté a inhibitory   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• novinové články MeSH

BACKGROUND: Dysfunction of the carnitine system in non-tumour tissue following anticancer therapy has been reported. In this setting, supplementation with carnitine derivatives might increase the general metabolic activity of normal cells so that they might better withstand the adverse effects of chemotherapy aimed at tumour cells. Here we investigated the effect of acetyl-L-carnitine (ALC) alone and in combination with the antineoplastic agent mitoxantrone (MX) in an animal cancer model. METHODS: The effects of MX and MX-ALC were assessed based on gain or loss of body weight and on local growth of a solid form of Ehrlich tumour inoculated into mice. We also performed biochemical analyses like serum activities of some enzymes signalling the functioning of the liver, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Total protein, albumin and bilirubin were also determined in serum. Under favourable conditions, the Ehrlich tumour readily forms metastases, and this is the reason why we performed histological studies of samples of both the liver and heart in order to identify changes that may have mediated the observed effect of the treatment. In addition to those studies, the survival time of treated animals against controls was also noted. RESULTS: MX monotherapy was associated with lower body weight gain, fewer metastases, smaller tumour size, and lower dissemination. ALC alone promoted survival, but had no potentiating effect on MX therapy in terms of survival. Serum biochemistry changes associated with MX-ALC treatment consisted of a significant (p < 0.05) increase in AST with MX at 6 or 9 mg·kg(-1) plus ALC 200 mg·kg(-1) and a significant (p < 0.05) reduction in total protein compared to the corresponding MX group; serum albumin and bilirubin remained unchanged. CONCLUSION: ALC in combination with MX, regardless of the dose of MX, led to higher occurrences of metastases with dissemination to the kidneys, lungs, heart, and mediastinum compared to MX treatment alone. These histological findings indicate that ALC is inappropriate to combine with MX in the treatment of a solid cancer. The protective effect of ALC in combination therapy with the cytostatic drug MX was not supported in this study by our findings that the agent did not improve the therapeutic outcomes of MX therapy.

• MeSH
• acylkarnitin terapeutické užití   MeSH
• antitumorózní látky terapeutické užití   MeSH
• bilirubin krev   MeSH
• Ehrlichův tumor farmakoterapie   patologie   MeSH
• experimentální nádory jater farmakoterapie   patologie   MeSH
• mitoxantron terapeutické užití   MeSH
• myši MeSH
• sérový albumin analýza   MeSH
• tělesná hmotnost MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• aktivní transport účinky léků   MeSH
• Ca(2+)-Mg(2+)-ATPasa fyziologie   MeSH
• experimentální nádory jater enzymologie   farmakoterapie   sekundární   MeSH
• metastázy nádorů farmakoterapie   MeSH
• myši MeSH
• radiosenzibilizující látky farmakologie   MeSH
• vápník fyziologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH

• MeSH
• cyklocytidin farmakologie   škodlivé účinky   MeSH
• cytochromy metabolismus   MeSH
• experimentální nádory jater farmakoterapie   patofyziologie   MeSH
• jaterní mitochondrie enzymologie   metabolismus   účinky léků   MeSH
• játra fyziologie   metabolismus   účinky léků   MeSH
• krysa rodu rattus MeSH
• respirační komplex IV metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH