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Molecular Biology Offers Hope for New Therapies in Prostate Cancer
Posted November 6, 2002
D. Miller, M.D., Ph.D., P. Bates, Ph.D., and J. Trent, Ph.D., University of Louisville

The regiments of present day chemotherapy utilize drugs that are toxic to both the tumor and normal tissue. This toxicity can lead to temporarily incapacitating side effects (e.g., nausea, fatigue, and diarrhea), as well as long-term effects. Current treatments for prostate cancer can have dire consequences, such as bladder control problems and sexual dysfunctions. Drs Miller, Bates, and Trent (University of Louisville, Louisville, Kentucky) are exploiting molecular biology techniques to develop new drugs that will specifically target cancer cells. Using G-rich oligonucleotides, which are strings of guanosine (one of the components of DNA), the researchers were able to demonstrate an antiproliferation effect in cancer cell lines from prostate, lung, colon, skin, kidney, and breast. Cell lines derived from highly metastatic prostate cancer were sensitive to the G-rich oligonucleotide analog. To understand these effects and therefore produce better analogs, the mechanism of drug action was investigated. These studies show that the antiproliferative effect observed correlates to binding of the analog to nucleolin, an important molecule in the processing of genes to proteins. In addition, the G-rich oligonucleotide analogs have been found to modulate DNA replication through interaction with a protein called helicase, a known participant in DNA synthesis. Cancer cells are known to have aberrant expression of proteins responsible for DNA and protein synthesis. Taken together, these results offer new hope in the continuing battle against prostate cancer.

Publications:

Dapic V, Bates PJ, Trent JO, Rodger A, Thomas SD, Miller DM. 2002. Antiproliferative activity of G-quartet-forming oligonucleotides with backbone modifications. Biochemistry 41:3676-3685.

Xu X, Hamhouyia F, Thomas SD, Burke TJ, Girvan AC, McGregor WG, Trent JO, Miller DM, Bates PJ. 2001. Inhibition of DNA replication and induction of S phase cell cycle arrest by G-rich oligonucleotides. J. Biol. Chem. 276:43221-43230.

Bates PJ, Kahlon JB, Thomas SD, Trent JO, Miller DM. 1999. Antiproliferative activity of G-rich oligonucleotides correlates with protein binding. J. Biol. Chem. 274:26369-26377.

Link:

Abstract: G-Rich Oligonucleotides as Novel Therapeutic Agents for Prostate Cancer

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African Americans, Genetic Diversity, and Prostate Cancer
Posted August 26, 2002
Rick A Kittles, Ph.D., National Human Genome Center at Howard University, Washington, DC

African American men are known to have a higher risk of developing prostate cancer, present with disease at a higher stage, and have a worse outcome from the disease than non-African American men. The debate continues within the medical field about whether this disparity is due to biological, environmental, or behavioral factors, or a combination of these factors. As part of larger projects in African American genomic research, scientists at Howard University's National Human Genome Center have been studying the role of gene polymorphisms in prostate cancer incidence and severity in African American men. A slight change in sequence in the control region of the CYP17 gene, which plays an important role in androgen biosynthesis, was found to be significantly associated with increased prostate cancer risk and clinically advanced disease in African American men compared to control groups of either Nigerian men or European-American men. Studies with a different gene involved in testosterone deactivation, CYP3A4, initially found correlations between a mutation in a control region of this gene and prostate cancer. However, when the data were corrected for contributions of different ethnic groups that may be a part of the ancestry of the African American, no significant correlation was found between the CYP3A4 mutation and prostate cancer. The researchers at the National Human Genome Center are continuing these and other studies to find the influence of genomic variation on prostate cancer and other diseases that affect African Americans.

Publications:

Kittles RA, Chen W, Panguluri RK, Ahaghotu C, Jackson A, Adebamowo CA, Griffin R, Williams T, Ukoli F, Adams-Campbell L, Kwagyan J, Isaacs W, Freeman V, Dunston GM. 2002. CYP3A4-V and prostate cancer in African Americans: causal or confounding association because of population stratification? Hum. Genet. 110:553-560.

Kittles RA, Panguluri RK, Chen W, Massac A, Ahaghotu C, Jackson A, Ukoli F, Adams-Campbell L, Isaacs W, Dunston GM. 2001. Cyp17 promoter variant associated with prostate cancer aggressiveness in African Americans. Cancer Epidemiol. Biomarkers Prev. 10:943-947.

Kittles RA, Young D, Weinrich S, Hudson J, Aryropoulos G, Ukoli F, Adams-Campbell L, Dunston GM. 2001 Extent of linkage disequilibrium between the Androgen Receptor gene CAG and GGC repeats in human populations: Implications for prostate cancer risk. Hum. Genet. 109:253-261.

Link:

Abstract: Cladistic Association Analysis of Genetic Effects on Prostate Cancer in African Americans

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Prostate Cancer Nerve Interactions in Metastasis
Posted June 24, 2002
Gustavo E. Ayala, M.D., Baylor College Of Medicine

In prostate cancer, the most common way that cancer cells escape from the prostate (metastasize) is by traveling along the nerve cells. This process, termed perineural invasion, is similar to cars travelling on a highway; the prostate cancer cells travel along nerves that form a path or highway of least resistance. Beyond this purely mechanistic explanation, little is known about how this process occurs. Researchers at the Baylor College of Medicine are trying to understand this process by studying how prostate cancer cells interact with neural cells. They have demonstrated, with cultured cells, that prostate cancer cells actually cause nerve branches to grow directly toward them, establishing contact between the two cell types. Once in contact, the cancer cells travel along the nerve branches back to the main body of the nerve where they can metastasize to other parts of the body. It is noteworthy that these cultured cells wrap around nerve cells in the same manner that human prostate cancer wraps around nerves in the prostate. The researchers also observed that nerves grow more quickly in the presence of cancer cells, and that the prostate cancer cells grow more quickly in the presence of nerves. Such interactions are most likely controlled through chemical signaling pathways that have yet to be discovered. The researchers intend to further investigate if nerve-epithelial cell interactions are exclusive to prostate cancer, or if they can occur either in cancers of other organs (e.g., the pancreas or colon), or in benign conditions such as those associated with benign prostate hyperplasia. Understanding the specific mechanisms of these cancer cell/nerve cell interactions is key to developing therapeutic strategies that target the chemical factors that define the ability of prostate cancer to metastasize.

Publications:

Ayala GE, Wheeler TM, Shine HD, et al. 2001. In vitro dorsal root ganglia and human prostate cell line interaction: redefining perineural invasion in prostate cancer. The Prostate 49:213-223.

Link:

Abstract: Neuro-Epithelial Interactions in Prostate Carcinoma

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Homing in on Metastatic Prostate Cancer Cells
Posted February 27, 2002
Samuel R. Denmeade, M.D., The Johns Hopkins University

Few treatment choices exist for men with metastatic prostate cancer where androgen ablation therapy has failed. Furthermore, drugs that may be capable of killing metastatic cancer cells also kill normal noncancerous cells. Therefore, drugs and treatments that can specifically target and kill metastatic prostate tumor cells, wherever they are in the body, without causing damage to normal cells are urgently needed. Prostate Cancer Research Program researchers at the Johns Hopkins University, in collaboration with The Royal Danish School of Pharmacy, are addressing this critical issue. Their approach is to chemically transform active, cell-killing drugs into inactive forms (prodrugs) that will become activated only in areas of the body that contain the cancer cells. Specifically, these investigators are using a drug called thapsigargin that is a natural plant product that kills cells by inducing apoptosis. To target thapsigargin to kill only prostate cancer cells, the researchers have produced several different thapsigargin prodrugs that are activated into their active cell-killing forms by prostate-specific antigen and prostate-specific membrane antigen, proteins that are produced in high levels by prostate cancer cells. This work represents an exciting and promising approach to specifically target the potent cell-killing ability of a chemotherapeutic agent, thapsigargin, to prostate cancer cells while avoiding side effects to the rest of the body.

Publications:

Jakobsen CM, Denmeade SR, Isaacs JT, Gady A, Olsen CE, Christensen SB. 2001. Design, synthesis, and pharmacological evaluation of thapsigargin analogues for targeting apoptosis to prostatic cancer cells. J. Med. Chem. 44:4696-4703.

Khan SR and Denmeade SR. 2000. In vivo activity of a PSA-activated doxorubicin prodrug against PSA-producing human prostate cancer xenografts. Prostate 45: 80-83.

Link:

Abstract: Enzymatic Activation of Proteasome Inhibitor Prodrugs by Prostate-Specific Antigen as Targeted Therapy for Metastatic Prostate Cancer

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