epoetin-alfa and Melanoma

Epoetin alfa (EPO, PROCRIT) pharmacokinetics and pharmacodynamics were evaluated in children with malignant solid tumors receiving chemotherapy.. Children initially received IV EPO 600 IU/kg (max dose 40,000 IU) or placebo once weekly for 16 weeks. Dose was increased to 900 IU/kg (max dose 60,000 IU) for patients not achieving a 1 g/dl increase in hemoglobin by study week 3 or 4. Serial PK samples were collected for 24 hr after the first study dose, and after the 10th or 11th dose. Serum EPO concentrations were analyzed using an ELISA assay, and pharmacokinetics were evaluated using compartmental methods.. Twelve children participated; six (median age 15.2 years; range 9.3-18.6 years) were randomized to receive EPO. All children required dosage increases to 900 IU/kg due to no response. The median (range) apparent EPO AUC0-24 and clearance (CL) were 67.1 IU/ml.hr (13.8-102.6) and 0.26 L/hr/m2 (0.19-1.08), respectively. After the 10th or 11th EPO dose in four of these six EPO patients, the median (range) apparent AUC0-24 and CL of EPO was 126.5 IU/ml.hr (107.3-161.1) and 0.21 L/hr/m2 (0.15-0.25), respectively. No significant correlations were observed between pharmacokinetic parameters and pharmacodynamic effects.. EPO disposition in our patients was similar to other pediatric patient populations or adults receiving IV EPO. Interesting but insignificant trends were noted in pharmacodynamic effects.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; Chondrosarcoma; Dose-Response Relationship, Drug; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Injections, Intravenous; Male; Melanoma; Osteosarcoma; Placebos; Recombinant Proteins; Skin Neoplasms; Time Factors; Treatment Outcome

Erythropoietin (Epo) is widely used clinically to treat anemia associated with various clinical conditions including cancer. Data from several clinical trials suggest significant adverse effect of Epo treatment on cancer patient survival. However, controversy exists whether Epo receptor (EpoR) is functional in cancer cells. In this study, we demonstrated that EpoR mRNA expression was detectable in 90.1% of 65 melanoma cell lines, and increased copy number of the Epo and EpoR loci occurred in 30 and 24.6% of 130 primary melanomas, respectively. EpoR knockdown in melanoma cells resulted in diminished ERK phosphorylation in response to Epo stimulation, decreased cell proliferation and increased response to the inhibitory effect of hypoxia and cisplatin in vitro. EpoR knockdown significantly decreased melanoma xenograft size and tumor invasion in vivo. On the contrary, constitutive activation of EpoR activated cell proliferation pathways in melanoma cells and resulted in increased cell proliferation and resistance to hypoxia and cisplatin treatment in vitro. EpoR activation resulted in significantly larger xenografts with increased tumor invasion of surrounding tissue in vivo. Daily administration of recombinant Epo fails to stimulate melanoma growth in vivo, but the treatment increased vascular size in the xenografts. Increased local recurrence after excision of the primary tumors was observed after Epo treatment. Epo induced angiogenesis in Matrigel plug assays, and neutralization of Epo secreted by melanoma cells results in decreased angiogenesis. These data support that EpoR is functional in melanoma and EpoR activation may promote melanoma progression, and suggest that Epo may stimulate angiogenesis and increase survival of melanoma cells under hypoxic condition in vivo.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Disease Progression; DNA Copy Number Variations; Epoetin Alfa; Erythropoietin; Gene Knockdown Techniques; Humans; Melanoma; Mice; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction; Skin Neoplasms; Transcriptional Activation

Consorcial projects focused on 5 cancer types, breast-, colorectal-, head and neck- and pediatric cancers, and malignant melanoma. Breast cancer studies revealed unique splicing mechanisms concerning BRCA1. In sporadic breast cancers the involvement of DNA-repair genes was proved to be dependent on the histological type. Bone-metastatic tumors have been characterized by decreased NM23 and increased c-met and p53 expressions. C-erbB2 genotype of the primary tumor was not maintained frequently in bone metastases. Application of DNA-microarray and quantitative PCR technologies improved the prediction of therapeutic sensitivity of breast cancers. Colorectal cancer studies revealed regional inhomogenities (clusters) in various geographical regions of Hungary, which were distinct in the case of colonic and rectal cancers. To increase the sensitivity of fecal blood test of colorectal cancer screening, a new double-antibody test was developed and tested in a large cohort of patients. Genetic analysis revealed that hypermethylation is a significant factor in microsatellite instability which, and plays a role in silencing of APC and E-cadherin genes as well. The Hungarian pattern of TS polymorphism was also determined and was correlated not only with the efficacy of 5-FU treatment but with the progression of the disease as well. Population-based studies have been carried out in head and neck cancer patients (HNC) and smokers as well to reveal the genetic background of increasing tumor incidence. These studies revealed polymorphism in XRCC1/3 methylation enzyme gene which has preventive role. Other studies found frequent local immunosuppression in HNC patients. Studies indicated that the success of irradiation in this cancer type is dependent on the anti-vascular effects. Pediatric cancer studies determined the parameters of neuroblastoma screening based on VMA measurements. New splice variants of the WT1 gene involved in the monitoring of MRD of ALL patients was also described this year. We also obtained positive experimental data for the retinoic acid therapy of ALL. Melanoma studies extensively used DNA-microarray technology which identified 4 melanoma-specific and 2 melanoma progression-specific genes. In experimental human melanoma xenograft models we have identified 3 anti-metastatic agents: low molecular weight heparin, 2-methoxyestradiol and erythropoietin-alpha, where the later was characterized by specific effects on tumor vasculature.

Topics: 2-Methoxyestradiol; Adult; Animals; Antineoplastic Agents; Biomarkers, Tumor; Biomedical Research; Bone Neoplasms; Breast Neoplasms; Child; Colorectal Neoplasms; Disease Models, Animal; Disease Progression; DNA Methylation; Epoetin Alfa; Erythropoietin; Estradiol; Female; Gene Expression Regulation, Neoplastic; Gene Silencing; Genetic Markers; Head and Neck Neoplasms; Heparin, Low-Molecular-Weight; Humans; Hungary; Incidence; Male; Melanoma; Microsatellite Repeats; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Polymorphism, Genetic; Predictive Value of Tests; Recombinant Proteins; Transplantation, Heterologous

Treatment of metastatic melanoma with biochemotherapy results in the rapid onset of anemia, requiring blood transfusion in 9 of 13 (69%) patients. Prophylactic use of weekly subcutaneous recombinant epoetin alfa eliminated the need for transfusion in all but 1 of 21 (5%) patients.

Topics: Anemia; Blood Transfusion; Cost-Benefit Analysis; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Melanoma; Neoplasm Metastasis; Quality of Life; Recombinant Proteins