In the interest of improving cancer treatment, considerable attention has been placed on the modification of radiation damage. The interaction of a variety of chemotherapy and/or molecularly targeted agents with radiation is under study to determine if tumors can be made more sensitive or normal tissues more resistant to radiation treatment. The central aim is to identify approaches that will result in a net therapeutic gain, thus improving cancer treatment with radiation. One goal of the project is to define and better understand those aspects of tumor physiology, including cellular and molecular processes and the influence of the tumor microenvironment on treatment response. Two independent studies have been completed showing that radiation-induced gene expression profiles differ significantly for cells exposed in vitro versus the same cells growing as a solid tumor in vivo further underscoring the influence of the tumor microenvironment on the radiation response. Further we have shown that multi-fraction radiation delivery results in a more robust induction of genes than single dose radiation treatment, in particular the interferon-related genes including STAT-1. We will attempt to modulate these genes to determine their influence on multi-fraction radiation treatment. The ability to enhance the response of the tumor to radiation, without enhancing normal tissue within a given treatment field is desirable. We have recently shown that loratadine and guggulsterone enhance tumor cell radiation response in vitro. Preliminary mechanistic studies indicate that loratadine imposes a G2/M block in cell cycle (G2/M phases of the cell cycle are very radiosensitive) and guggulsterone, which appears to interfere with radiation-induced DNA damage repair. Evaluation of both agents in combination with radiation in tumor bearing mice is currently underway. We have also evaluated another molecularly targeted agent, which is a Chk-1 inhibitor. This agent provides considerable radiation enhancement of tumor cells in vitro and in vivo with very little to no normal tissue toxicity. The working hypothesis is that the agent abrogates the normal radiation-induced delay in G2 of the cell cycle, thus enhancing the radiation response because of incomplete repair of radiation damage. We have also shown that this agent directly inhibits radiation-induced damage repair using the H2AX assay. With respect to normal tissue response to radiation, it is widely known that the TGF beta signaling pathway is a major player in radiation-induced late effects (fibrosis). Our previous studies have shown that mice deficient in TGF beta signaling (Smad3 knock-out mice-downstream signaling intermediate in the TGF beta pathway) are resistant to fibrosis when treated with high dose radiation. Recent mouse normal tissue studies using a TGF beta type 1 receptor kinase inhibitor have shown marked reduction in radiation-induced soft tissue fibrosis. This agent blocks the TGF beta signaling pathway and current studies are centered in confirming that this agent impacts TGF beta signaling in vivo. Lastly we have preliminary pre-clinical data suggesting that the nitroxide, Tempol protects against radiation-induced oral mucositis. Oral mucositis is a common toxicity associated with the radiation treatment of head and neck cancers. The goal of these pre-clinical studies is to gain enough efficacy data to introduce these experimental agents into human radiation oncology clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC006321-29
Application #
7735357
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
29
Fiscal Year
2008
Total Cost
$448,821
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Samuni, Yuval; Cook, John A; Choudhuri, Rajani et al. (2010) Inhibition of adipogenesis by Tempol in 3T3-L1 cells. Free Radic Biol Med 49:667-73
Guo, Zhanjun; Tsai, Mong-Hsun; Shiao, Yih-Horng et al. (2008) DNA (cytosine-5)-methyltransferase 1 as a mediator of mutant p53-determined p16(ink4A) down-regulation. J Biomed Sci 15:163-8
Soule, Benjamin P; Hyodo, Fuminori; Matsumoto, Ken-Ichiro et al. (2007) The chemistry and biology of nitroxide compounds. Free Radic Biol Med 42:1632-50
Soule, Benjamin P; Hyodo, Fuminori; Matsumoto, Ken-Ichiro et al. (2007) Therapeutic and clinical applications of nitroxide compounds. Antioxid Redox Signal 9:1731-43
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Simone, Nicole L; Soule, Benjamin P; Gerber, Lynn et al. (2007) Oral Pirfenidone in patients with chronic fibrosis resulting from radiotherapy: a pilot study. Radiat Oncol 2:19
Matsumoto, Ken-Ichiro; Szajek, Lawrence; Krishna, Murali C et al. (2007) The influence of tumor oxygenation on hypoxia imaging in murine squamous cell carcinoma using [64Cu]Cu-ATSM or [18F]Fluoromisonidazole positron emission tomography. Int J Oncol 30:873-81

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