American Association for Cancer Research

March 15 2008 Clinical Cancer Research Highlights

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Selected Articles from the March 15, 2008 Issue

The articles referenced in this Highlights section will be available online in HTML and PDF formats to all interested users at no charge until the next issue of Clinical Cancer Research is published. Click on the article title to view the complete article.

View the Table of Contents for the March 15 issue of Clinical Cancer Research.


CCR Focus:
New Cytotoxics in Oncology

Teicher et al. et al.

Page 1610

It has been suggested that the era of cytotoxic agents is coming to a close, superceded by the era of targeted therapies. This issue of CCR Focus strives to show that cytotoxic agents cannot be counted out in the war against cancer. Guest Editor Beverly A. Teicher brought together six articles underscoring the development of new cytoxic agents in clinical oncology. New mechanisms, new agents, and a new paradigm in which inhibiting a target will result in cytotoxicity if the drug’s target is critical to maintaining the malignant phenotype are all explored by the contributing authors. 
 

p53 Isoforms Implicated in Melanoma Drug Resistance

Avery-Kiejda et al.

Page 1659

The tumor suppressor gene p53 plays an important role in the cellular response to DNA damage. p53 is known to be mutated in many cancers, and p53 mutation is associated with resistance to chemotherapy. Metastatic melanoma is largely unresponsive to DNA damaging chemotherapy agents, even though wild-type p53 is frequently detected. To further examine the role of p53 in melanoma, Avery-Kiejda and colleagues analyzed the expression of p53 and its isoforms in a panel of human melanoma cell lines. The p53 isoforms p53b and Δ40p53 were expressed in the majority of melanoma cell lines, but were absent or expressed at low levels in fibroblasts and melanocytes. Δ40p53 was shown to inhibit both basal and Cisplatin-induced p53-dependent transcription of p21 and PUMA, suggesting a novel mechanism for the restricted function of wild-type p53 in melanoma. 


Targeting NFκB in Multiple Myeloma

Suvannasankha et al.

Page 1814

Constitutively activated nuclear factor kappa B (NFκB) is known to confer apoptotic resistance in multiple myeloma (MM). In this study, Suvannasankha and colleagues explored the therapeutic potential of the NFκB inhibitor parthenolide on MM cells in the context of a bone marrow microenvironment. They found that parthenolide shows considerable anti-tumor activity against a broad spectrum of MM cell lines and primary samples. Parthenolide selectively inhibited growth of MM cell lines and primary cells, overcame the proliferative effects of the cytokines IL-6 and IGF-1, and blocked IL-6 secretion from bone marrow stromal cells. Additionally, parthenolide treatment altered the balance between pro- and anti-apoptotic proteins, and led to increased apoptosis in MM cells. These experiments provide a rationale for the clinical development of parthenolide in multiple myeloma therapy. 


Resveratrol is an antioxidant found in a wide variety of plant species, including grapes. Here, Roccaro and colleagues show that resveratrol exhibits anti-neoplastic activity against Waldenström’s Macroglobulinemia (WM) primary cells. After resveratrol treatment, they observed a down-regulation of Akt, ERK/MAPK and Wnt signaling pathways and a reduction of Akt activity, which triggered activation of JNK and activation of intrinsic and extrinsic caspase pathways. Adherence to bone marrow stromal cells did not confer protection to WM cells against resveratrol-induced cytotoxicity. Furthermore, resveratrol showed synergistic cytotoxicity when combined with other agents widely used to fight WM. These preclinical data provide a rationale for evaluating the efficacy of resveratrol to treat WM in the clinic. 


Bacterial Antitumor Activity Mediated by TLR4 

Lee et al.

Page 1905

The bacterium Salmonella has previously been shown to have activity as a tumor-targeting anticancer agent in mouse models. Salmonella likely elicits antitumor effects by stimulating the immune system, but the specific immune mechanism through which Salmonella acts remains unclear. It is known, however, that Toll-like receptor 4 (TLR4) is a signaling receptor for lipopolysaccharides found on Salmonella. Lee and colleagues used wild-type mice and TLR4-deficient mice to study the role of TLR4 in the antitumor immune response induced by Salmonella. They found that Salmonella elicited chemokine expression, immune cell recruitment, and antiangiogenic activities via TLR4 signaling. These findings provide a clearer molecular understanding of how Salmonella stimulates the immune system to fight tumors.


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