http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16380506&dopt=Abstract

Mol Cancer Res. 2005 Dec;3(12):685-91.

Interleukin-12 up-regulates Fas expression in human osteosarcoma and Ewing's sarcoma cells by enhancing its promoter activity.

Zhou Z, Lafleur EA, Koshkina NV, Worth LL, Lester MS, Kleinerman ES.

Division of Pediatrics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.

Interleukin-12 (IL-12) has shown significant antitumor activity in several preclinical animal tumor models. Our previous studies showed that IL-12 inhibited tumor growth in human osteosarcoma and Ewing's sarcoma animal model. Decreased Fas expression in osteosarcoma increased the lung metastatic potential. In this study, we further examined the mechanism of IL-12 antitumor activity and showed that IL-12 significantly increased Fas expression in both human osteosarcoma cells LM7 and Ewing's sarcoma cells TC71. Up-regulation of Fas expression increased their sensitivity to Fas-induced cell apoptosis. Constructs of the Fas promoter linked to a luciferase reporter gene were used to determine the promoter activity. IL-12 increased Fas promoter activity 4.2- and 4.9-fold in TC71 and LM7 cells, respectively. Time course studies have shown that recombinant IL-12 stimulated Fas promoter activity at 2 hours, reached the peak level at 4 hours, and then declined at 24 hours. To investigate whether IL-12 specifically enhanced Fas promoter activity, we determined whether another gene (E1A) was able to stimulate Fas promoter activity. We also evaluated effect of IL-12 on the topoisomerase IIalpha promoter. The results indicated that E1A but not IL-12 stimulated topoisomerase IIalpha promoter activity. E1A failed to increase Fas promoter activity. We also found that kappaB-Sp1 element at position -295 to -286 in Fas promoter was essential for IL-12-induced activation, and nuclear factor-kappaB transcription factor was activated after IL-12 treatment in TC71 cells. These results indicate that IL-12 up-regulates Fas expression in human osteosarcoma and Ewing's sarcoma by enhancing Fas promoter activity. Understanding this mechanism may lead to new therapeutic approaches for the treatment of sarcoma involving the use of IL-12.

PMID: 16380506 [PubMed - indexed for MEDLINE]

Pediatr Blood Cancer. 2005 Nov 29

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16317751&query_hl=1

Full Text of Article: http://www3.interscience.wiley.com/cgi-bin/abstract/112163116/ABSTRACT

Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma

Division of Hematology/Oncology, Primary Children's Medical Center, Salt Lake City, Utah.
Lars M. Wagner, MD (1) *, Nancy McAllister, MD (1), Robert E. Goldsby, MD (1), Aaron R. Rausen, MD (3), René Y. McNall-Knapp, MD (4), M. Beth McCarville, MD (5), Karen Albritton, MD (1) (2)

(1)  Division of Hematology/Oncology, Primary Children's Medical Center, Salt Lake City, Utah
(2)  Division of Oncology, Huntsman Cancer Institute, Salt Lake City, Utah
(3)  Division of Pediatric Hematology/Oncology, New York University Medical Center, New York, New York
(4)  Division of Pediatric Hematology/Oncology, University of Oklahoma Health Sciences Center, Oklahoma
(5)  Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee
email: Lars M. Wagner (lars.wagner@cchmc.org)

*Correspondence to Lars M. Wagner, Division of Hematology/Oncology, MLC 7015, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229

BACKGROUND: Preclinical models show sequence-dependent synergy with the combination of temozolomide and irinotecan, and a Phase I trial has demonstrated the combination to be tolerable and active in children with relapsed solid tumors. Because responses were seen in patients with Ewing sarcoma (ES) on that trial, additional patients were treated with this combination following study completion. PROCEDURE: We reviewed data from all ES patients treated with temozolomide and irinotecan at four institutions, including seven patients treated on the above Phase I trial. RESULTS: Sixteen patients received a total of 95 courses, with a median of five courses per patient. All patients had either progressive disease (PD) during initial therapy (n = 5) or relapse within 2 years of diagnosis (n = 11). Twelve patients had metastatic disease at diagnosis, including 5 with bone and/or marrow metastases. Patients received oral temozolomide 100 mg/m(2)/day on days 1-5 plus intravenous irinotecan 10-20 mg/m(2)/day on days 1-5 and 8-12, with courses repeated every 21-28 days. We observed 1 complete, 3 partial, and 3 minor responses in 14 evaluable patients, with a median duration of response of 30 weeks. Planned 21-day courses were tolerable and no more toxic than 28-day courses. Myelosuppression was minimal despite heavy pretreatment. Grade 3-4 diarrhea occurred in 11% of courses and was related to higher irinotecan doses. Over 600 irinotecan doses were administered uneventfully at home. CONCLUSIONS: Temozolomide and protracted intravenous irinotecan given in 21-day courses was tolerable and active in patients with advanced ES. Home administration of irinotecan with temozolomide was safe and is reasonable palliative therapy. A formal Phase II study using a uniform dose and schedule is warranted to better define activity. (c) 2005 Wiley-Liss, Inc.

PMID: 16317751 [PubMed - as supplied by publisher]