ABO-incompatible heart transplantation in early childhood: An international multicenter study of clinical experiences and limits.

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ABO-incompatible heart transplantation in early childhood: An international multicenter study of clinical experiences and limits.

J Heart Lung Transplant. 2013 Jan 7;

Authors: Urschel S, Larsen IM, Kirk R, Flett J, Burch M, Shaw N, Birnbaum J, Netz H, Pahl E, Matthews KL, Chinnock R, Johnston JK, Derkatz K, West LJ

Abstract
BACKGROUND: Intentional blood group (BG)-incompatible (ABOi) heart transplantation in childhood is emerging in many centers. Safety limits remain undetermined. In this multicenter study we have compiled experience on clinical and immunologic boundaries. METHODS: Data from six centers in Europe and North America on ABOi transplantation were collected in a standardized survey. RESULTS: Fifty-eight ABOi transplants were performed in 57 patients. Median age at transplant was 6.8 months (0.03 to 90 months); post-transplant follow-up was 37.7 months (0.46 to 117 months), accumulating 188 patient-years. Forty-seven percent of the patients received pretransplant mechanical circulatory support. Donors were either blood group A (n = 25), B (n = 18) or AB (n = 15). The median peak antibody titer to the donor BG pretransplant was 1:8 (0 to 1:64) for anti-A and 1:4 (0 to 1:32) for anti-B. Titers against the donor BG were lower post- than pretransplant in B recipients (p = 0.02), whereas third-party antibodies in BG O recipients developed normally post-transplant. Induction immunosuppression included anti-thymocyte globulin (61%), basiliximab (32%) or none (7%). All patients received calcineurin inhibitors, including 62% with mycophenolate mofetil, 10% with azathioprine, 2% with everolimus and 24% with steroids. There were 4 episodes of cellular rejection (Grade?2R) and 7 antibody-mediated rejections. Five patients underwent antibody removal post-transplant. One patient developed severe graft vasculopathy. Freedom from death or retransplantation was 100%/96%/69% at 1/5/10 years. No graft loss was attributed to BG antibodies. CONCLUSIONS: Successful ABOi heart transplantation can be performed at an older age and with higher isohemagglutinin titers than initially assumed and using similar immunosuppressive regimens as for ABO-compatible transplants. Rejection and graft vasculopathy are rare. Persistently low titers of antibodies to the donor BG post-transplant suggest elements of tolerance and/or accommodation.

PMID: 23305695 [PubMed - as supplied by publisher]

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Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.

Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.

J Transl Med. 2012 Dec 10;10(1):245

Authors: Chen ZY, Shi M, Peng LX, Wei W, Li XJ, Guo ZX, Li SH, Zhong C, Qian CN, Guo RP

Abstract
ABSTRACT: BACKGROUND: Dovitinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptors and platelet-derived growth factor receptor beta. Dovitinib is currently in clinical trials for the treatment of hepatocellular carcinoma (HCC). METHOD: In this study, we used five HCC cell lines and five endothelial cell lines to validate molecular and cellular targets of dovitinib. RESULTS: Tumor growth and pulmonary metastasis were significantly suppressed in an orthotopic HCC model. Immunoblotting revealed that among known dovitinib targets, only PDGFR-beta was expressed in two HCC cell lines, while four of five endothelial lines expressed PDGFR-beta, FGFR-1, and VEGFR-2. Dovitinib inhibited endothelial cell proliferation and motility at 0.04 mumol/L, a pharmacologically relevant concentration; it was unable to inhibit the proliferation or motility of HCC cells at the same concentration. Immunohistochemical analyses showed that dovitinib significantly decreased the microvessel density of xenograft tumors, inhibiting proliferation and inducing apoptosis in HCC cells. CONCLUSION: Our findings indicate that dovitinib inhibits HCC growth and metastasis preferentially through an antiangiogenic mechanism, not through direct targeting of HCC cells.

PMID: 23228017 [PubMed - as supplied by publisher]

c-met inhibitors zm-447439 rad001

Disposition and metabolism of 14C-dovitinib (TKI258), an inhibitor of FGFR and VEGFR, after oral administration in patients with advanced solid tumors.

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Disposition and metabolism of 14C-dovitinib (TKI258), an inhibitor of FGFR and VEGFR, after oral administration in patients with advanced solid tumors.

Cancer Chemother Pharmacol. 2012 Nov;70(5):653-63

Authors: Dubbelman AC, Upthagrove A, Beijnen JH, Marchetti S, Tan E, Krone K, Anand S, Schellens JH

Abstract
PURPOSE: This study investigated the metabolism and excretion of dovitinib (TKI258), a tyrosine kinase inhibitor that inhibits fibroblast, vascular endothelial, and platelet-derived growth factor receptors, in patients with advanced solid tumors.
METHODS: Four patients (cohort 1) received a single 500 mg oral dose of (14)C-dovitinib, followed by the collection of blood, urine, and feces for ?10�days. Radioactivity concentrations were measured by liquid scintillation counting and plasma concentrations of dovitinib by liquid chromatography-tandem mass spectrometry. Both techniques were applied for metabolite profiling and identification. A continuous-dosing extension phase (nonlabeled dovitinib 400�mg daily) was conducted with the 3 patients from cohort 1 and 9 additional patients from cohort 2.
RESULTS: The majority of radioactivity was recovered in feces (mean 61�%; range 52-69�%), as compared with urine (mean 16�%; range 13-21�%). Only 6-19�% of the radioactivity was recovered in feces as unchanged dovitinib, suggesting high oral absorption. (14)C-dovitinib was eliminated predominantly via oxidative metabolism, with prominent primary biotransformations including hydroxylation on the fluorobenzyl ring and N-oxidation and carbon oxidation on the methylpiperazine moiety. Dovitinib was the most prominent radioactive component in plasma. The high apparent volume of distribution (2,160 L) may indicate that dovitinib distributes extensively to tissues. Adverse events were predominantly mild to moderate, and most common events included nausea, vomiting, constipation, diarrhea, and fatigue.
CONCLUSIONS: Dovitinib was well absorbed, extensively distributed, and eliminated mainly by oxidative metabolism, followed by excretion, predominantly in feces. The adverse events were as expected for this class of drug.

PMID: 23010851 [PubMed - indexed for MEDLINE]

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Interaction between polymorphisms of DNA repair genes significantly modulated bladder cancer risk.

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Interaction between polymorphisms of DNA repair genes significantly modulated bladder cancer risk.

Int J Med Sci. 2012;9(6):498-505

Authors: Zhi Y, Yu J, Liu Y, Wei Q, Yuan F, Zhou X, Song B, Chen Z, Yang J

Abstract
DNA repair is a primary defense mechanism against damage caused by exogenous and endogenous sources. We examined the associations between bladder cancer and 7 polymorphisms from 5 genes involved in the maintenance of genetic stability (MMR: MLH1-93G>A; BER: XRCC1--77T>C and Arg399Gln; NER:XPC Lys939Gln and PAT +/-; DSBR:ATM G5557A and XRCC7 G6721T) in 302 incident bladder cancer cases and 311 hospital controls. Genotyping was done using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. The homozygous variant of XRCC7 G6721T (Odds Ratio [OR]: 2.36; 95% Confidence Interval [CI]: 1.13-4.92) was associated with increased bladder cancer risk. In an analysis of combined genotypes, the combination of XRCC1Arg399Gln (Gln allele) with XRCC1-77 T/T led to an increase in risk (OR: 1.61; 95% CI: 1.10-2.36). Moreover, when the XPCLys939Gln (Gln allele) (nucleotide excision repair [NER]) was present together with XRCC7 (T allele) (double strand break repair [DSBR]), the bladder cancer risk dramatically increased (OR: 4.42; 95% CI: 1.23-15.87). Our results suggest that there are multigenic variations in the DNA repair pathway involved in bladder cancer susceptibility, despite the existence of ethnic group differences.

PMID: 22927776 [PubMed - indexed for MEDLINE]

coxinhibitors c-met inhibitors zm-447439

Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.

Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.

J Transl Med. 2012 Dec 10;10(1):245

Authors: Chen ZY, Shi M, Peng LX, Wei W, Li XJ, Guo ZX, Li SH, Zhong C, Qian CN, Guo RP

Abstract
ABSTRACT: BACKGROUND: Dovitinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptors and platelet-derived growth factor receptor beta. Dovitinib is currently in clinical trials for the treatment of hepatocellular carcinoma (HCC). METHOD: In this study, we used five HCC cell lines and five endothelial cell lines to validate molecular and cellular targets of dovitinib. RESULTS: Tumor growth and pulmonary metastasis were significantly suppressed in an orthotopic HCC model. Immunoblotting revealed that among known dovitinib targets, only PDGFR-beta was expressed in two HCC cell lines, while four of five endothelial lines expressed PDGFR-beta, FGFR-1, and VEGFR-2. Dovitinib inhibited endothelial cell proliferation and motility at 0.04 mumol/L, a pharmacologically relevant concentration; it was unable to inhibit the proliferation or motility of HCC cells at the same concentration. Immunohistochemical analyses showed that dovitinib significantly decreased the microvessel density of xenograft tumors, inhibiting proliferation and inducing apoptosis in HCC cells. CONCLUSION: Our findings indicate that dovitinib inhibits HCC growth and metastasis preferentially through an antiangiogenic mechanism, not through direct targeting of HCC cells.

PMID: 23228017 [PubMed - as supplied by publisher]

rad001 ecdysone chir-258

Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.

Dovitinib preferentially targets endothelial cells rather than cancer cells for the inhibition of hepatocellular carcinoma growth and metastasis.

J Transl Med. 2012 Dec 10;10(1):245

Authors: Chen ZY, Shi M, Peng LX, Wei W, Li XJ, Guo ZX, Li SH, Zhong C, Qian CN, Guo RP

Abstract
ABSTRACT: BACKGROUND: Dovitinib is a receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor receptors, fibroblast growth factor receptors and platelet-derived growth factor receptor beta. Dovitinib is currently in clinical trials for the treatment of hepatocellular carcinoma (HCC). METHOD: In this study, we used five HCC cell lines and five endothelial cell lines to validate molecular and cellular targets of dovitinib. RESULTS: Tumor growth and pulmonary metastasis were significantly suppressed in an orthotopic HCC model. Immunoblotting revealed that among known dovitinib targets, only PDGFR-beta was expressed in two HCC cell lines, while four of five endothelial lines expressed PDGFR-beta, FGFR-1, and VEGFR-2. Dovitinib inhibited endothelial cell proliferation and motility at 0.04 mumol/L, a pharmacologically relevant concentration; it was unable to inhibit the proliferation or motility of HCC cells at the same concentration. Immunohistochemical analyses showed that dovitinib significantly decreased the microvessel density of xenograft tumors, inhibiting proliferation and inducing apoptosis in HCC cells. CONCLUSION: Our findings indicate that dovitinib inhibits HCC growth and metastasis preferentially through an antiangiogenic mechanism, not through direct targeting of HCC cells.

PMID: 23228017 [PubMed - as supplied by publisher]

dovitinib dna-pk coxinhibitors

Acquired resistance to sunitinib in human renal cell carcinoma cells is mediated by constitutive activation of signal transduction pathways associated with tumour cell proliferation.

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Acquired resistance to sunitinib in human renal cell carcinoma cells is mediated by constitutive activation of signal transduction pathways associated with tumour cell proliferation.

BJU Int. 2013 Jan 10;

Authors: Sakai I, Miyake H, Fujisawa M

Abstract
WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Although there have been a few studies investigating the molecular mechanism mediating the acquisition of resistance to molecular-targeted agents, including sunitinib, by renal cell carcinoma (RCC) cells, this mechanism remains largely unclear. The maintenance of protein kinase activation during sunitinib treatment may be involved in the acquisition of a phenotype resistant to sunitinib in RCC, and additional treatment with agents targeting activated protein kinases could be a promising approach for overcoming resistance to sunitinib in RCC. OBJECTIVE: To characterise the mechanism involved in the acquired resistance to sunitinib, a potential inhibitor of multiple receptor tyrosine kinases (RTKs), in renal cell carcinoma (RCC). MATERIALS AND METHODS: A parental human RCC cell line, ACHN (ACHN/P), was continuously exposed to increasing doses of sunitinib, and a cell line resistant to sunitinib (ACHN/R), showing an ?5-fold higher IC(50) (concentration that reduces the effect by 50%) than that of ACHN/P, was developed. RESULTS: ACHN/R appeared to acquire significant cross resistance to sorafenib; however, there were no significant differences in sensitivities to the Mammalian target of rapamycin inhibitors, temsirolimus and everolimus, between ACHN/P and ACHN/R. After sunitinib treatment, the expression levels of phosphorylated Akt and p44/42 mitogen-activated protein kinase in ACHN/P, but not those in ACHN/R, were significantly inhibited. RTK assay showed that treatment of ACHN/P with sunitinib resulted in the marked downregulation of several phosphorylated RTKs compared with that of ACHN/R. Additional treatment with a specific inhibitor of Akt significantly increased the sensitivity of ACHN/R to sunitinib, but not that of ACHN/P. There were no significant differences between in vivo growth patterns of ACHN/P and ACHN/R in mice before and after the administration of sunitinib; however, the proportion of cells positive for TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) staining in ACHN/P tumour was significantly greater than that in ACHN/R tumour in mice treated with sunitinib. CONCLUSION: The maintenance of protein kinase activation during sunitinib treatment may be involved in the acquisition of resistant phenotype to sunitinib in RCC cells.

PMID: 23305097 [PubMed - as supplied by publisher]

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