NASA Scientific and Technical Aerospace Reports

affect survival of various cancer cell types, including breast cancer cells. Our hypothesis is that activation of NF-icB in breast
cancer cells contributes to a G2/M cell cycle arrest, affording these cell extra opportunity to repair damaged DNA and thus
allowing them to evade death inducing effects of radiation. Cell cycle analysis and levels of apoptosis were determined
following exposure to ionizing irradiation. Cells capable of NF-xB activation efficiently arrested in G2/M cell cycle phase
while those that are not capable of activating NF-icB, do not efficiently arrest. Using RPA analysis, we identified a gene,
p21(wafl1/Cipl1), and have now shown that it is involved in maintaining the G2/M phase cell cycle arrest following IR.
Through the use of stable RNAi interference, we found that the G2/M arrest is partially dependent on p21(wafl/ Cipl).
Understanding how NF-icB is activated and how NF-KB provides protection from cell death will be important for designing
strategies to circumvent this resistance mechanism to improve efficacy of radiation therapy.
DTIC
Cancer; Cells (Biology); Mammary Glands
20040111631 Mayo Clinic, Rochester, MN
A Phase II Immunotherapeutic Trial: Combination Androgen Ablative Therapy and CTLA-4 Blockade as a Treatment
for Advanced Prostate Cancer
Kwon, Eugene D.; Dec. 2003; 8 pp.; In English
Contract(s)/Grant(s): DAMD17-02-1-0245
Report No.(s): AD-A425731; No Copyright; Avail: CASI; A02, Hardcopy
The induction of tumor-specific T cells remains a primary obstacle to immunotherapeutic approaches for most cancers
including prostate cancer. This difficulty has been largely ascribed to mechanisms for tumor evasion of the immune system
and host-imposed restrictions (collectively referred to as tolerance) that prevent cross-reactive autoimmunity against the parent
tissues from which tumors arise. Limitations in techniques to identify novel and truly immunogenic prostate- specific antigens
and efficient methods to modify autologous tissues for vaccine preparation have further constrained approaches to develop
immune-based therapies for prostate cancer. Hence, relatively straightforward manipulations that induce specific T cell
responses against prostate tumors or epithelial tissues, especially in vivo, might ultimately prove valuable for prostate cancer
immunotherapy. This study explores combined androgen ablation (AA) + CTLA-4 blockade immunotherapy as a means of
potentiating T cell-mediated responses against prostate tumors to improve overall treatment of advanced prostate cancer.
DTIC
Ablation; Cancer; Cells (Biology); Hormones; Males; Prostate Gland; Therapy
20040111632 Texas Univ. Health Science Center, San Antonio, TX
The Role of Ubiquitin-Mediated Proteolysis of Cyclin D in Breast Cancer
Block, Karen L.; Apr. 2004; 45 pp.; In English
Contract(s)/Grant(s): DAMD17-2-1-0583
Report No.(s): AD-A425732; No Copyright; Avail: CASI; A03, Hardcopy
Cyclin D is a positive regulator of the cell cycle and is found to be highly expressed in breast cancer cells. Cyclin D is
post-transcriptionally regulated by the ubiquitin mediated protein degradation pathway. CDC34, a ubiquitin conjugating
enzyme, and SCF (Skpl, Cullin, F-box, ring protein), a ubiquitin ligase, are postulated to be the specific E2 and E3 enzymes
which target Cyclin D for ubiquitination. It is currently unclear how regulation of the CDC34-SCF complex may modulate
Cyclin D proteolysis. In this regard, we have studied the regulation of CDC34 by phosphorylation and by CDC34-associated
proteins as well as the interaction of CDC34 with the SCF components, Cull and Roci. Our results suggest that the
carboxyl-terminal acidic tail domain of CDC34 does not appear to be critical for its interactions with Cull and Roci in an in
vitro binding assay, while the role of CDC34 phosphorylation on Cull and Roci binding is still unclear. Currently, our work
has focused on identifying the proteins which tightly associate with CDC34 and which are required for DNA replication
initiation in Xenopus egg extracts. We are developing strategies to purify the CDC34- associated proteins from human HeLa
cell extracts and from Xenopus egg extracts. We predict that these previously unidentified CDC34-associated proteins will
play an important role in regulating the ubiquitination of cyclin D in vivo.
DTIC
Cancer; Cells (Biology); Cycles; Mammary Glands
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