http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16135484&query_hl=3


J Clin Oncol. 2005 Sep 1;23(25):6172-6180.

    Phase I and Pharmacokinetic Study of Gefitinib in Children With Refractory Solid Tumors: A Children's Oncology Group Study.

    Daw NC, Furman WL, Stewart CF, Iacono LC, Krailo M, Bernstein ML, Dancey JE, Speights RA, Blaney SM, Croop JM, Reaman GH, Adamson PC.

    Department of Hematology-Oncology, Mail Stop 260, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; e-mail: najat.daw@stjude.org.

    PURPOSE Epidermal growth factor receptor is expressed in pediatric malignant solid tumors. We conducted a phase I trial of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in children with refractory solid tumors. PATIENTS AND METHODS Gefitinib (150, 300, 400, or 500 mg/m(2)) was administered orally to cohorts of three to six patients once daily continuously until disease progression or significant toxicity. Pharmacokinetic studies were performed during course one (day 1 through 28). Results Of the 25 enrolled patients, 19 (median age, 15 years) were fully evaluable for toxicity and received 54 courses. Dose-limiting toxicity was rash in two patients treated with 500 mg/m(2) and elevated ALT and AST in one patient treated with 400 mg/m(2). The maximum-tolerated dose was 400 mg/m(2)/d. The most frequent non-dose-limiting toxicities were grade 1 or 2 dry skin, anemia, diarrhea, nausea, and vomiting. One patient with Ewing's sarcoma had a partial response. Disease stabilized for 8 to >/= 60 weeks in two patients with Wilms' tumor and two with brainstem glioma (one exophytic). At 400 mg/m(2), the median peak gefitinib plasma concentration was 2.2 mug/mL (range, 1.2 to 3.6 mug/mL) and occurred at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance and median half-life were 14.8 L/h/m(2) (range, 3.8 to 24.8 L/h/m(2)) and 11.7 hours (range, 5.6 to 22.8 hours), respectively. Gefitinib systemic exposures were comparable with those associated with antitumor activity in adults. CONCLUSION Oral gefitinib is well tolerated in children. Development of the drug in combination with cytotoxic chemotherapy will be pursued.

    PMID: 16135484 [PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16121404&dopt=Abstract

http://www3.interscience.wiley.com/cgi-bin/abstract/111082718/ABSTRACT

Cancer. 2005 Aug 24; [Epub ahead of print]     Related Articles, Links
  
    Zoledronic acid inhibits primary bone tumor growth in Ewing sarcoma.

    Zhou Z, Guan H, Duan X, Kleinerman ES.

    Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
    email: Eugenie S. Kleinerman (ekleiner@mail.mdanderson.org)

*Correspondence to Eugenie S. Kleinerman, Division of Pediatrics, Unit 87, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, Fax: (713) 794-5042

    BACKGROUND: Zoledronic acid has been shown to be effective in the treatment of osteoporosis, hypercalcemia, and metastatic bone tumors. The efficacy of zoledronic acid on primary bone tumors has not been investigated. METHODS: A primary bone tumor mouse model was established. Intratibia injection of TC71 cells resulted in an osteolytic bone tumor. Four days after injection the mice were treated with zoledronic acid alone, paclitaxel alone, or zoledronic acid plus paclitaxel. Control mice were treated with phosphate-buffered saline. Bone tumor growth was assessed using a Faxitron Specimen Radiography System. The gene expression was detected by reverse-transcription polymerase chain reaction (RT-PCR), ELISA, and immunohistochemistry. Osteoclast formation was determined by tartrate-resistant acid phosphatase (TRAP) staining. RESULTS: Zoledronic acid induced apoptosis in TC71 human Ewing sarcoma cells and inhibited cell proliferation. Five weeks after injection, 89% of mice in the control group developed osteolytic bone tumors. Paclitaxel had little effect on bone tumor growth, with 78% of mice developing tumors. By contrast, 44% of mice treated with zoledronic acid developed bone tumors. The most effective treatment was zoledronic acid plus paclitaxel. Tumor incidence in the combination therapy group was only 22%. Osteoclasts were quantified using TRAP staining. There was a decrease in TRAP-positive osteoclasts in tumor tissues from zoledronic acid-treated animals compared to control animals. RT-PCR, immunohistochemistry, and ELISA assay demonstrated that zoledronic acid up-regulated osteoprotegerin expression. CONCLUSIONS: These results suggest that zoledronic acid induces apoptosis and inhibits primary bone tumor growth in Ewing sarcoma through a mechanism involving the up-regulation of osteoprotegerin. Zoledronic acid may provide a novel therapeutic approach for the treatment of patients with Ewing sarcoma. Cancer 2005. (c) 2005 American Cancer Society.

    PMID: 16121404 [PubMed - as supplied by publisher]