- Advancing Breast Cancer Diagnosis through New Imaging Techniques
- Managing Cancer Pain through Gene Therapy
- Predictors of Follow-up after an Abnormal Mammogram
- Inhibition of Breast Cancer Cell Growth by Citrus Limonoids
- Particle-Mediated IL-12 Gene Transfer in Breast Cancer
Breast cancer survival can be highly dependent on detection and therapeutic intervention. By enhancing present imaging techniques, it is hoped that through highly precise mammography, tumors may be detected during the earliest stages of development. The use of advanced mammographic techniques could decrease the need for invasive diagnostic procedures such as needle biopsy. A novel technique called Diffraction Enhanced Imaging is being studied for its usefulness in breast cancer diagnosis. Dr. L.D. Chapman of the Illinois Institute of Technology (Chicago, Illinois) co-developed this method in medical imaging and is now applying it to breast cancer studies. By expanding the capabilities of Diffraction Enhanced Imaging, more information has been extracted, thus leading to improved imaging of the complex tissue matrix making up the breast. This new technique allows for high-contrast images to be acquired by using refracted and scattered x-ray beams in addition to the absorption of conventional mammography. These advances in medical imaging will actually permit a dose reduction of x-rays since the optimization of the refraction and scatter contrast occur where absorption (or delivered dose) is low. Additionally, these studies show a correlate of Diffraction Enhanced Imaging with conventional histology diagnosis from breast biopsy samples. This technical development holds new promise for early detection of breast cancer.
Dilmanian FA, Zhong Z., Ren B., Wu XY, Chapman LD, Orion I, Thomlinson WC. 2000. Computed tomography of x-ray index of refraction using the diffraction enhanced imaging method. Phys. Med. Biol 45(4): 933-46.
Pisano ED, Johnston RE, Chapman D, Geradts J, Iacocca MV, Livasy CA, Washburn DB, Sayers DE, Zhong, Z, Kiss MZ, Thomlinson WC. 2000. Human breast cancer specimens: diffraction-enhanced imaging with histologic correlation - improved conspicuity of lesion detail compared with digital radiography. Radiology 214(3): 895-901
Hasnah MO, Zhong Z, Oltulu O, Pisano E, Johnston RE, Sayers D, Thomlinson W, Chapman D. 2002. Diffraction enhanced imaging contrast mechanisms in breast cancer specimens, Med. Phys. 29 (10): 2216-2221.
Traditional pain management for patients with advanced breast cancer has relied on the prescription of drugs such as morphine. Treatments used for chronic pain are self-limiting due to side effects and efficacy issues. Patients develop tolerance to opiates and must be prescribed larger quantities of the drug to relieve debilitating pain. Current published studies suggest a role for many intracellular molecules in mediating pain signaling. In an experimental gene therapy study by Dr. J. Yang, formerly of the University of Rochester (Rochester, New York), antisense oligonucleotides to one such molecular mediator of pain, protein kinase C-g, were shown to inhibit signaling pain pathways in the rat animal model. These 'backward' gene sequences are able to block chronic pain by silencing the active conversion of genes to their products, proteins. An analgesic effect of antisense oligonucleotides to protein kinase C-g was observed when an inflammatory pain response was present in rats. Since cancer pain is associated with a strong neuropathological signaling component in nerve cells, this study demonstrates the significance of gene therapy in inhibiting pain by blocking the production of proteins that carry pain signals. The broad therapeutic ramifications in pain management for advanced breast cancer and other chronic pain syndromes are clear.
Wu C, Garry M, Zollo R, Yang J. 2001. Novel targets for gene therapy in the management of pain, Part I: Strategies and Methods. Anesthesiol 94:1119-32.
Wu C, Garry M, Zollo R, Yang J. 2001. Novel targets for gene therapy in the management of pain, Part II: Molecular Targets. Anesthesiol 95:216-240.
An estimated 60% of women that have an abnormal mammogram do not return for further medical evaluation. Breast Cancer Research Program investigator Dr. Alexis Bakos, while attending Johns Hopkins University as a graduate student, conducted this study to determine why some women with abnormal mammograms do not return for evaluative follow-up care. Cox's Interaction Model of Client Health Behavior was used as a framework. The study sample included 75 women. Forty-four women who returned for diagnostic follow-up and 31 women who had not returned were interviewed using a telephone survey method to determine which variables predicted follow-up care and most accurately classified women into either category. Those who returned for diagnostic follow-up after their abnormal mammogram cited four major reasons. These were: (1) health promotion, (2) influence of family, (3) influence of others, and (4) fear as a motivator. Those who did not return for diagnostic follow-up cited six major reasons. These were: (1) avoidance, (2) lack of health insurance coverage, (3) inconvenience, (4) stress of an illness, (5) denial of the need to return, and (6) fear as a barrier. A major outcome of this study was identifying factors related to the decision of whether to obtain follow-up care after an abnormal mammogram. This information can be used to design intervention strategies to increase the number of women that return for diagnostic follow-up.
Citrus limonoids are a class of chemically related compounds present in citrus fruit. Limonoids have been shown to have anti-cancer activity and can inhibit breast cancer cellular proliferation in estrogen receptor negative (ER-) and positive (ER+) cells. In this study, Breast Cancer Research Program investigators injected nude mice with either ER- or ER+ human breast cancer cells that were allowed to establish solid tumors. The mice were given limonoids to observe their effects on the proliferation of established and resected tumors, respectively. The researchers found that limonoids, particularly limonin, slowed tumor growth and were able to prevent or delay the regrowth of resected tumors in these models. Limonoids also reduced the incidence of lung metastases. There was a differential effect of limonoids on ER- and ER+ tumors. The investigators also studied the mechanism by which limonoids inhibit cellular proliferation. Citrus limonoids induced cell cycle arrest in G2M, but the relative potency was different for each limonoid. These compounds did not induce apoptosis. These results suggest that citrus juice components may be beneficial in the prevention of mammary cancer.
Tumor metastasis in visceral organs is the leading cause of death in breast cancer patients. Progress in cancer research suggests that immunotherapy, a form of therapy that stimulates the patient's own immune system to destroy cancerous cells, offers a promising strategy for the treatment of metastatic breast cancer. One approach involves boosting the existing antitumor immune response with the use of cytokines, such as interleukin-12 (IL-12). However, in early clinical trials using IL-12, systemic administration of the cytokine resulted in severe side effects in patients. Using a new approach developed at PowderJect Vaccines, Inc, Dr. Yang and colleagues explored a gene therapy based approach to minimize side effects, called particle-mediated gene transfer, for the treatment of metastatic breast cancer. Particle-mediated gene transfer is accomplished by the delivery of DNA-coated gold particles directly into skin cells in vivo. Transfected cells then produce the gene product (in this case IL-12) from the DNA injected into them. Results from this study (1) suggest that particle-mediated IL-12 gene therapy, alone or in combination with other immunological approaches, may be a promising treatment of breast cancer and (2) have paved the way for the first clinical trial using in vivo particle-mediated gene transfer initiated at the University of Wisconsin.
Oshikawa K, Rakhmilevich AL, Shi F, Sondel PM, Yang N, and Mahvi DM. 2001. Interleukin 12 gene transfer into skin distant from the tumor site elicits antimetastatic effects equivalent to local gene transfer. Human Gene Therapy, 20;12(2):149-60.
Rakhmilevich, AL, Janssen, K, Hao, Z, et al. 2000. Interleukin 12 gene therapy of a weakly immunogenic mouse mammary carcinoma results in reduction of spontaneous lung metastases via a T cell-independent mechanism. Cancer Gene Therapy, 7:826-838.
Rakhmilevich, AL, and Yang, NS. 2000. In vivo particle-mediated gene transfer for cancer therapy. In Gene Therapy of Cancer: Methods and Protocols, editors Walther and Stein, Berlin. Human Press, Inc., 331-344.
Rakhmilevich, AL, Timmins, JG, Janssen, K, et al., 1999. Gene gun-mediated IL-12 gene therapy induces antitumor effects in the absence of toxicity: A direct comparison with systemic IL-12 protein therapy. J. Immunother. 22:135-144.
Oshikawa, K, Shi, F, Rakhmilevich, AL, et al. 1999. Synergistic inhibition of tumor growth in a murine mammary adenocarcinoma model by combinational gene therapy using interleukin-12, pro-interleukin-18 and IL-1b-converting enzyme cDNA. Proc. Natl. Acad. Sci. USA, 96:13351-13356