Research Programs
Cancer Center faculty are dedicated to excellence in patient care, community outreach, education and research. Research efforts are particularly important because they are the keys to finding new treatment and curative therapies. Here are examples of current research projects.
Experimental Bone Marrow Transplantation & Immunotherapy Research Program
Breast Cancer Program | Healthy Communities Partnership for Cancer Prevention
Center for International Blood & Marrow Transplant Research | Biophysics
Investigators in the Experimental Bone Marrow Transplantation and Immunotherapy Research Program include James Casper, PhD, Bryon Johnson, PhD, David Margolis, MD, Rimas Orentas, PhD, Jeffrey Woodliff, PhD, James LaBelle, PhD, and Robert Truitt, PhD, in Pediatrics - Hematology/Oncology, William Drobyski, MD, Carolyn Keever Taylor, PhD, and Subramaniam Malarkannan, PhD, in Medicine - Hematology/Oncology, and Joel Shilyansky, MD, in Pediatric Surgery.
Research goals of the group are 1) to conduct high quality basic research in bone marrow transplant (BMT) that can be translated to clinical settings, 2) to gain insight into immunological mechanisms that contribute to the success or failure of BMT, and 3) to develop and explore novel approaches in immunotherapy.
The group is composed of actively funded clinical and basic research scientists, capable of taking problems encountered in the management of patients back to the laboratory to gain a better understanding of the cellular and molecular mechanisms involved. As insights are gained in the laboratory, this knowledge is converted into novel or improved treatment strategies.
Translational research efforts of the program have contributed to practical applications and effective interventions in cancer-bearing patients, resulting in a clinical BMT program that is among the national leaders. Dr. Casper, Dr. Drobyski and Dr. Margolis helped pioneer the use of donor leukocyte infusions (DLI) as a treatment for leukemia relapse after a bone marrow transplant.
This innovative approach provided the most direct proof to date of the tumor-killing benefits of cellular immunotherapy and provided physicians, for the first time, with a tool to treat patients whose cancer relapsed after a BMT. Dr. Margolis is funded by the NCI to identify and characterize at a molecular level the lymphocytes responsible for the antitumor effect.
Dr. Drobyski is investigating a novel approach using gene therapy to control the detrimental immune reactivity of T lymphocytes given for DLI therapy. He directs a clinical trial that uses retroviral vectors to transfer the thymidine kinase "suicide" gene into lymphocytes and has developed a transgenic animal model to explore other uses for this approach with grant support from the NHLBI.
Bryon Johnson is funded by NCI to develop preclinical animal models to determine the cellular mechanisms responsible for the success of DLI therapy after BMT and to evaluate strategies to improve the antitumor efficacy.
Another NCI grant supports the work of Dr. Johnson with Dr. Truitt in testing strategies to induce donor/host tolerance after BMT and the consequences for relapse in patients with leukemia. An NHLBI exploratory grant supports the collaboration of Dr. Truitt, Dr. Johnson, Dr. Drobyski, and Dr. Margolis with Dr. Jeffrey Woodliff and Carolyn Keever Taylor, PhD (Medicine – Hem/Onc) in searching for human immunoregulatory cells in BMT patients that are similar to those described by Dr. Johnson in preclinical animal models of BMT/DLI. Such cells are thought to control autoimmune reactions in a non-transplant setting and graft-vs-host reactions in the setting of BMT as well as antitumor responses.
In 2000, Dr. Johnson received the McCulloch and Till Award for the best basic science article published in Biology of Blood and Marrow Transplantation. In 1999, Dr. Drobyski received the George Santos Award for the best clinical science article published in BBMT.
Dr. Orentas leads a translational research effort focused on adoptive cellular immunotherapy of lymphomas using genetically modified T cells. He and Johnson are also conducting preclinical testing of cancer vaccines created by the fusion of neuroblastoma cells. They are also combining efforts with Dr. Truitt and Dr. LaBelle to look at the effects of gene therapy using CD80 and CD86 co-stimulatory molecules on tumor vaccines.
Dr. Shilyansky's research is focused on developing effective cancer therapies by directing the patient's immune response to cancer cells. He is spearheading efforts to develop clinical vaccines to neuroblastoma. Shilyansky's research is supported in part by the Elsa U. Pardee Foundation as well as th Florence and Marshall Schwid Endowment for Sarcoma Research. In preclinical studies, he is investigating the role of CD4+ T-lymphocytes in helping or hindering the immune system's response to cancer cells. These cells may be critical to the success of clinical trials in immunotherapy.
The research of Dr. Malarkannan is focused on understanding the molecular mechanisms of antigen processing and presentation as well as the role of T cells in tumor and transplant rejection using minor histocompatibility antigens as model systems. Dr. Malarkannan is supported by the American Cancer Society, the American Society for Blood and Marrow Transplantation, and the Roche Organ Transplant Research Fund.
The Experimental BMT and Immunotherapy Research Program is supported by the Midwest Athletes Against Childhood Cancer (MACC) Fund as well as peer-reviewed grants from the NIH, ACS and private foundations.
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Here are representative clinical, basic and translational research publications by members of the Experimental BMT and Immunotherapy Research Programs over the past five years:
- Johnson BD, Konkol MC, Truitt RL: CD25+ Immunoregulatory T Cells of Donor Origin Suppress Alloreactivity after BMT. Biology of Blood and Marrow Transplantation. In press, 2002.
- Johnson BD, Taylor PA, Stankowski MC, Talib S, Hearst JE, Blazar BR: Photochemical Treatment of Donor Lymphocytes Inhibited Their Ability to Facilitate Donor Engraftment or Increase Donor Chimerism after Nonmyeloablative Conditioning or Establishment of Mixed Chimerism. Biology of Blood and Marrow Transplantation. In press, 2002.
- Bin,Q, Johnson BD, Schauer D, Orentas RJ: Production of Macrophage Migration Inhibitory Factor (MIF) by Human and Murine Neuroblastoma. Tumor Biology. In press, 2002.
- Keever-Taylor CA: Process control: application to the cell processing laboratory. Cytotherapy 2:63-73, 2002.
- Levine JE, Braun T, Penza SL, Beatty P, Cornetta K, Martino R, Drobyski WR, Barrett AJ, Porter DL, Giralt S, Leis J, Holmes HE, Johnson M, Horowitz M, Collins RH Jr.: Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation. Journal of Clinical Oncology 20:405-12, 2002.
- LaBelle JA and Truitt RL: Characterization of a murine NKT cell tumor previously described as an acute myelogenous leukemia. Leukemia & Lymphoma 43:1637-44, 2002.
- LaBelle JA, Hanke CA, Blazar BR and Truitt RL: Negative effect of CTLA-4 in vivo on induction of T-cell immunity to B7-1+, but not B7-2+, murine acute myelogenous leukemia. Blood 99:2146-53, 2002.
- Bunin N, Carston M, Wall D, Adams R, Casper J, Kamani N, King R. Unrelated marrow transplantation for children with acute lymphoblastic leukemia in second remission. Blood. 99:3151-7, 2002.
- Drobyski WR, Klein J, Flomenberg N, Pietryga D, Vesole DH, Margolis DA, Keever-Taylor CA. Superior survival associated with transplantation of matched unrelated versus one-antigen-mismatched unrelated or highly human leukocyte antigen-disparate haploidentical family donor marrow grafts for the treatment of hematologic malignancies: establishing a treatment algorithm for recipients of alternative donor grafts. Blood 99:806-14, 2002.
- Keever-Taylor CA, Craig A, Molter M, Fu P, Loebel A, Skonecki J, Zeng H, Giesen B. Complement-mediated T-cell depletion of bone marrow: comparison of T10B9.1A-31 and Muromonab-Orthoclone OKT3. Cytotherapy 3:467-81, 2001.
- Choi EY, Yoshimura Y, Christianson GJ, Sproule TJ, Malarkannan S, Shastri N, Joyce S, Roopenian DC. Quantitative analysis of the immune response to mouse non-MHC transplantation antigens in vivo: the H60 histocompatibility antigen dominates over all others. Journal of Immunology 166:4370-9, 2001.
- Orentas RJ, Schauer D, Bin Q and Johnson BD: Electrofusion of a weakly immunogenic neuroblastoma with dendritic cells produces a tumor vaccine. Cellular Immunology 213:4-13, 2001.
- Johnson BD, Dagher N, Stankowski MC, Hanke CA and Truitt RL: Donor NK (NK1.1+) cells do not play a role in GVL and GVH reactions after DLI. Biology of Blood and Marrow Transplantation 7:589-595, 2001.
- Orentas RJ, Roskopf SJ, Nolan GP, Nishimura MI. Retroviral transduction of a T cell receptor specific for an Epstein-Barr virus-encoded peptide. Clin Immunol. 98:220-8, 2001.
- Drobyski WR, Morse HC 3rd, Burns WH, Casper JT, Sandford G. Protection from lethal murine graft-versus-host disease without compromise of alloengraftment using transgenic donor T cells expressing a thymidine kinase suicide gene. Blood. 97(8):2506-13, 2001.
- Keever-Taylor CA, Bredeson C, Loberiza FR, Casper JT, Lawton C, Rizzo D, Burns WH, Margolis DA, Vesole DH, Horowitz M, Zhang MJ, Juckett M, Drobyski WR. Analysis of risk factors for the development of GVHD after T cell-depleted allogeneic BMT: effect of HLA disparity, ABO incompatibility, and method of T-cell depletion. Biol Blood Marrow Transplant 7:620-30, 2001.
- Keever-Taylor CA, Klein JP, Eastwood D, Bredeson C, Margolis DA, Burns WH, Vesole DH. Factors affecting neutrophil and platelet reconstitution following T cell-depleted bone marrow transplantation: differential effects of growth factor type and role of CD34(+) cell dose. Bone Marrow Transplant. 27:791-800, 2001.
- Keever-Taylor CA, Margolis D, Konings S, Sandford GR, Nicolette CA, Lawendowski C, Burns WH. Cytomegalovirus-specific cytolytic T-cell lines and clones generated against adenovirus-pp65-infected dendritic cells. Biol Blood Marrow Transplant. 7:247-56, 2001.
- Malarkannan S, Mendoza LM, Shastri N. Generation of antigen-specific, lacZ-inducible T-cell hybrids. Methods Mol Biol. 156:265-72, 2001.
- Porter DL, Collins RH Jr, Hardy C, Kernan NA, Drobyski WR, Giralt S, Flowers ME, Casper J, Leahey A, Parker P, Mick R, Bate-Boyle B, King R, Antin JH. Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions. Blood. 95(4):1214-21, 2000.
- Drobyski WR, Vodanovic-Jankovic S, Klein J. Adoptively transferred gamma delta T cells indirectly regulate murine graft-versus-host reactivity following donor leukocyte infusion therapy in mice. J Immunol 165:1634-40, 2000.
- Margolis DA, Casper JT, Segura AD, Janczak T, McOlash L, Fisher B, Miller K, Gorski J. Infiltrating T cells during liver graft-versus-host disease show a restricted T-cell repertoire. Biol Blood Marrow Transplant. 6(4):408-15, 2000.
- Margolis DA, Casper JT. Alternative-donor hematopoietic stem-cell transplantation for severe aplastic anemia. Semin Hematol. 37(1):43-55, 2000.
- Drobyski WR. Evolving strategies to address adverse transplant outcomes associated with T cell depletion. J Hematother Stem Cell Res 9:327-37, 2000.
- Malarkannan S, Horng T, Eden P, Gonzalez F, Shih P, Brouwenstijn N, Klinge H, Christianson G, Roopenian D, Shastri N. Differences that matter: major cytotoxic T cell-stimulating minor histocompatibility antigens. Immunity. 13:333-44, 2000.
- Johnson BD, Becker EE and Truitt RL: Graft-versus-host and graft-versus-leukemia reactions following delayed infusions of donor T-subsets. Biology of Blood and Marrow Transplantation 5:123-132, 1999.
- Truitt RL, Johnson BD, Hanke C, Talib S and Hearst JE: Photochemical treatment with S-59 psoralen and ultraviolet A light to control the fate of naive or primed T lymphocytes in vivo after allogeneic bone marrow transplantation. Journal of Immunology 163:5145-5156, 1999.
- Johnson BD, Becker EE, LaBelle JL, and Truitt RL: Role of immunoregulatory donor T cells in suppression of graft-versus-host disease following donor leukocyte infusion therapy. Journal of Immunology, 163:6479-6487, 1999.
- Drobyski WR, Hessner MJ, Klein JP, Kabler-Babbitt C, Vesole DH, Margolis DA, Keever-Taylor CA. T-cell depletion plus salvage immunotherapy with donor leukocyte infusions as a strategy to treat chronic-phase chronic myelogenous leukemia patients undergoing HLA-identical sibling marrow transplantation. Blood 94(2):434-41, 1999.
- Orentas RJ, Rospkopf SJ, Casper JT, Getts RC, Nilsen TW. Detection of Epstein-Barr virus EBER sequence in post-transplant lymphoma patients with DNA dendrimers. J Virol Methods 77:153-63, 1999.
- Malarkannan S, Horng T, Shih PP, Schwab S, Shastri N. Presentation of out-of-frame peptide/MHC class I complexes by a novel translation initiation mechanism. Immunity. 10:681-90, 1999.
- Drobyski WR. Adoptive immunotherapy using donor leukocyte infusions to treat relapsed hematologic malignancies after allogeneic bone marrow transplantation. Cancer Treat Res 101:233-66, 1999.
- Burt RK, Drobyski WR, Traynor AE, Link CJ Jr. Herpes simplex thymidine kinase (HStk) transgenic donor lymphocytes. Bone Marrow Transplant 24:1043-51, 1999.
- Drobyski WR, Majewski D, Hanson G. Graft-facilitating doses of ex vivo activated gammadelta T cells do not cause lethal murine graft-vs.-host disease. Biol Blood Marrow Transplant 5:222-30, 1999.
- Johnson BD, Hanke CA, Becker EE and Truitt RL: Sca1+/Mac1+ nitric oxide-producing cells in the spleens of recipients early following bone marrrow transplant suppress T cell responses in vitro. Cellular Immunology 189:149-159, 1998.
- Link CJ Jr. Burt RK. Traynor AE. Drobyski WR. Seregina T. Levy JP. Gordon L. Rosen ST. Burns WH. Camitta B. Casper J. Horowitz M. Juckett M. Lawton C. Margolis D. Pietryga D. Rowlings P. Taylor C. Furtado M. Stefka J. Gupta Burt S. Kaiser H. Vesole DH. Adoptive immunotherapy for leukemia: donor lymphocytes transduced with the herpes simplex thymidine kinase gene for remission induction. Human Gene Therapy. 9(1):115-34, 1998.
- Juckett M. Rowlings P. Hessner M. Keever-Taylor C. Burns W. Camitta B. Casper J. Drobyski WR. Hanson G. Horowitz M. Lawton C. Margolis D. Peitryga D. Vesole D. T cell-depleted allogeneic bone marrow transplantation for high-risk non-Hodgkin's lymphoma: clinical and molecular follow-up. Bone Marrow Transplantation. 21:893-9, 1998.
- Drobyski WR, Pelz C, Kabler-Babbitt C, Hessner M, Baxter-Lowe LA, Keever-Taylor CA. Successful unrelated marrow transplantation for patients over the age of 40 with chronic myelogenous leukemia. Biol Blood Marrow Transplant. 4(1):3-12, 1998.
- Malarkannan S, Shih PP, Eden PA, Horng T, Zuberi AR, Christianson G, Roopenian D, Shastri N. The molecular and functional characterization of a dominant minor H antigen, H60. J Immunol. 161:3501-9, 1998.
- Orentas RJ. Determination of Epstein-Barr virus (EBV) load by RT-PCR and cellular dilution. Mol Cell Probes 12:427-30, 1998.
- Drobyski WR, Hessner MJ. The use of the polymerase chain reaction to predict for subsequent relapse in unrelated marrow transplantation for chronic myelogenous leukemia. Leuk Lymphoma 31:317-23, 1998.
- Drobyski WR, Majewski D, Ozker K, Hanson G. Ex vivo anti-CD3 antibody-activated donor T cells have a reduced ability to cause lethal murine graft-versus-host disease but retain their ability to facilitate alloengraftment. J Immunol 161:2610-9, 1998.
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Breast Cancer Program
The central problem in breast cancer is that we do not understand the molecular events that lead to its 1) development, 2) invasion, and 3) metastasis. We recognize our limited ability to identify patients who are at risk for developing breast cancer, to identify occult systemic metastatic disease, and to develop new effective treatment strategies.
Breast cancer patients currently receive poorly tailored therapies that are beneficial to a proportion of the patients. The breast cancer program objectives are to understand the fundamental pathogenic mechanisms of breast cancer development and to use these scientific discoveries for novel clinical research programs to improve the diagnosis and treatment of this disease.
Through Froedtert Hospital and other hospitals throughout southeastern Wisconsin there are patients who have either early or advanced disease and who are available for epidemiologic, preventive and therapeutic investigations.
There are four program themes.
Pathogenesis
The first is understanding the mechanisms of breast cancer pathogenesis. The following Medical College of Wisconsin investigators focus on the role of hormonal signaling in the regulation of cell proliferation, signaling pathways of oncogenes and tumor suppressors and molecular events that lead to invasion and angiogenesis:
Rolf Jacobi, PhD
Hyperactive p21-activated protein kinase gamma-PAK in breast cancer.
Sonia Sugg, MD
Use of transgenic mouse model with a regulatable estrogen receptor (ER) to estrogen receptor.
Bahiru Gametchu, PhD, DVM
Signal Transduction pathways initiated via a plasma membrane receptor for estrogen receptor.
Cecilia Hillard, PhD
Studies of antiproliferative effects of the cannabinoid and G-protein coupled receptor (GPGR).
Yoshiki Iwamoto, PhD
Identification of leptin-STAT3 pathway in breast cancer angiogenesis using DNA microarray analysis.
Ashwanni Khana, MD
Role of TGR-beta and inflammation in breast cancer.
Ravi Misra, PhD
Role of DNA binding by BRCA1 in the control of P21 expression.
Sally Twining, MD
Mechanism of interaction of the tumor suppressor, maspin, with the cell surface of mammary carcinoma cells.
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Immunotherapeutics
The second theme includes immunotherapeutics with a goal of understanding the role of the immune response in the treatment of this disease. These investigations can potentially lead to novel vaccine or cellular therapies:
Bryon Johnson, PhD
Allospecific immunoregulatory T-cells in BMT recipients.
Mary Otterson, MD
Pathology immunomodulation of breast cancer.
Experimental Therapeutics
The third theme involves laboratory investigations for breast cancer. Results from these studies can lead to novel clinical trials:
Christopher Chitambar, MD
Iron proteins and the hemochromatosis (HFE) gene in breast cancer: roles in tumor growth and response to tamoxifen and cytotoxic chemotherapy.
Fritz Sieber, PhD
Cytotoxic Se(0)-protein conjugates for the treatment of breast cancer.
James Rizzo, MD
Autologenic stem cell transplantation for metastatic breast cancer.
Cancer Control/Prevention
The fourth theme focuses on cancer control and prevention. A number of important projects focus on greater access to screening and early detection. The attempt is to identify high-risk patient populations who are either at risk for developing breast cancer or identify social and demographic barriers to early detection:
Geoffrey Lamb, MD
Medicine screening mammograms.
Karen Brasel, MD, MPH
Surgery, decision analysis of prophylactic tamoxifen vs. close follow-up for
women at increased risk of developing breast cancer.
Marilyn Schapira, MD, MPH
The effect of a computer based breast cancer risk counseling program on risk
perceptions and mammography screening use.
Philip N. Redlich, MD, PhD
Ductal lavage.
Kenneth Schellhase, MD, MPH
Surveillance care in older breast cancer survivors.
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Healthy Communities Partnership for Cancer Prevention
Healthy Communities Partnership for Cancer Prevention (HCPCP) is a community-academic partnership that develops cancer prevention programs to improve the health of the Milwaukee communities. The partnership is led by Syed M. Ahmed, MD, MPH, DrPH, associate professor and associate director of the Center for Healthy Communities.
The Center for Healthy Communities is part of the Department of Family and Community Medicine. Cheryl A. Maurana, PhD, is director. To learn more about the Center for Healthy Communities, go to www.family.mcw.edu/communities.htm.
HCPCP's Partners
- Medical College of Wisconsin Cancer Center
- Center for Healthy Communities
- Froedtert Hospital
- Holy Cathedral Church of God in Christ
Church-Based Program
Dr. Ahmed, Dr. Maurana, Tracy Williams and Jacqueline Sills-Ware have launched the Church-Based Program, which is HCPC's initial cancer prevention program. The purpose of the Church-Based Program is to promote cancer prevention through churches.
As churches are identified, Dr. Ahmed has introduced the Community-Based Participatory Research (CBPR) model to create and establish the program. This model provides a foundation for building community leadership and community health. Churches are engaged in the planning and implementation of the program. This model also encourages quality assurance, because there will be ongoing analysis and staggered implementation of the program.
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Holy Cathedral Church of God in Christ
Many churches have a strong community presence and are active in meeting the needs of the community. As the HCPCP strategically identified such churches in Milwaukee, Holy Cathedral Church of God in Christ, under the leadership of Pastor C.H. McClelland, was selected as the first church of the Church-Based Program.
The kick-off occurred May 5, 2002, on the church's annual Family Day. Representatives of HCPCP and the church worked together to introduce the new partnership to the church congregation.
Surveys were completed by members of the congregation that day. Analysis of the survey results will guide the partnership in planning an effective program that will not only increase cancer knowledge, but also encourage healthy lifestyles that will promote cancer prevention.
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Center for International Blood and Marrow Transplant Research
The Center for International Blood and Marrow Transplant Research (CIBMTR), a part of the Health Policy Institute at the Medical College of Wisconsin, was originally established in 1972 to collect and analyze data on allogeneic bone marrow transplants.
Today, the CIBMTR is the largest center of its kind in the world. It took its current form in 2004 as a partnership between the National Marrow Donor Program® and the Medical College of Wisconsin's International Bone Marrow Transplant Registry and Autologous Blood and Marrow Transplant Registry.
The CIBMTR, in collaboration with the National Marrow Donor Program and the EMMES Corp., received a five-year, $11 million grant from the National Institutes of Health (NIH) to serve as the Data and Coordinating Center for a new national Blood and Marrow Transplant Clinical Trials Network. The Network links 16 US transplant program consortia to perform clinical trials focused on blood and marrow transplant therapy. This project is led by Mary Horowitz, MD, MS, Christopher Bredeson, MD, MS, and John Klein, PhD. Dr. Klein is professor and head of the Division of Biostatistics at the Medical College of Wisconsin.
The CIBMTR databases include information on more than 150,000 transplant recipients who were treated at approximately 500 transplant centers in 47 countries. Using these data, the Registries conduct pioneering research in blood and marrow transplantation worldwide.
By studying large numbers of transplants from around the world, the CIBMTR can learn in months what otherwise could take years. These studies have contributed to the extraordinary progress in blood and marrow transplantation over the past three decades.
The CIBMTR responds to hundreds of requests each year from transplant specialists worldwide who need very specific data on transplant strategies and results. Because of the Center's sophisticated statistical research, physicians quickly receive information grouped by disease, gender, age and other factors to help them make better decisions about the best treatment for their patients.
Patients can also contact the CIBMTR to learn of transplant data related to their situations, thereby giving them a measure of confidence and control in their treatment.
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Biophysics: Free Radical Mechanism of Apoptosis
– Potential Ways to Improve Cancer Therapy and Decrease Drug Toxicity
The researchers in this program are investigator Balaraman Kalyanaraman, PhD, professor and director of the Biophysics Research Institute; and co-investigators Christopher Chitambar, MD, professor of hematology and neoplastic diseases, and Shi-Jiang Li, PhD, professor of biophysics.
Doxorubicin is one of the most widely used antitumor agents in the treatment of solid tumors and other types of cancers including breast and prostate cancers. Unfortunately, its clinical efficacy is severely hampered by a dose-limiting cardiotoxicity, which manifests as congestive heart failure and cardiomyopathy. Children treated for leukemia with doxorubicin develop heart problems in their adult years long after the cessation of doxorubicin chemotherapy.
Emerging research suggests that cancer patients receiving Herceptin as a second-line therapy for breast cancer, following doxorubicin treatment as a first-line therapy, developed cardiac problems. Recent studies suggest that myocardial dysfunction caused by doxorubicin treatment may involve myocyte apoptosis through formation of oxy radicals. Apoptosis in myocardium eventually leads to congestive heart failure due to systematic reduction in the amount of cardiomyocytes. Thus, a continuous non-invasive monitoring of hearts during doxorubicin treatment may reveal new mechanistic insight and lead to new therapeutic interventions.
Greater understanding of the biochemical mechanism of apoptosis itself will lead to the understanding of the relationship between apoptosis threshold and increased resistance to drugs in cancer therapy.
Techniques to monitor non-invasively in vivo progression of doxorubicin-induced apoptosis and cardiomyopathy in small animals have been lacking. The impaired contractile function of doxorubicin-treated rodents is presently monitored ex vivo in isolated rat or mouse hearts from doxorubicin-treated animals.
The availability of a non-invasive imaging technique that will measure repeated, reproducible assessment of in vivo cardiac function will greatly benefit researchers in free radical/apoptosis research. Recently, magnetic resonance imaging (MRI/1.5 T) has emerged as a potentially valuable technique for evaluating ventricular function and myocardial tissue cell volume fraction both in animals and humans. In contrast to transthoracic echocardiography, MRI provides a volumetric 3-dimensional evaluation of the left ventricular function. In addition, the onset of myocyte apoptosis can be quantitatively measured by diffusion-weighted MR imaging.
Recent literature suggests that apoptosis of cardiac myocytes is responsible for several cardiac diseases. Inhibition of doxorubicin-induced myocyte apoptosis could slowly prevent or slow the loss of contractile myocardial cells. Several antioxidants (e. g., free radical traps) are able to inhibit doxorubicin-induced cardiotoxicity. The hypothesis is that interventions that prevent cardiomyocyte apoptosis will protect the heart function. In this study we will investigate the efficacy of antioxidants in small animals through non-invasive imaging of myocardium.
We will use the state-of-the-art gradient coil technology and with improved spatial and temporal resolution, we will develop reliable MRI criteria for monitoring doxorubicin-induced apoptotic cell death in rodent models in response to antioxidant treatment.
Enhancing cancer cell suicide or apoptosis: Apoptosis or programmed cell death plays a significant role in cancer therapy. Uncontrolled apoptosis has been implicated in cancers and leukemia's where there is insufficient apoptosis and in neurodegenerative diseases associated with excessive apoptosis. In cancers, up-regulation of anti-apoptotic proteins (e. g., Bcl-2) suppresses apoptosis.
Strategies to selectively enhance the endogenous apoptotic machinery or activate apoptosis directly by drugs in cancer cells are therefore highly desirable. Ongoing research using the state-of-the art chemical, biophysical, and molecular biological techniques suggest that free radicals induced apoptotic signaling machinery is much different in cancer cells as compared to normal cells. Efforts are underway to understand the mechanism of regulation of the pro- and anti-apoptotic stimuli in these cells.
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