Programmatic Themes:

1. Functional Magnetic Resource (fMR) Imaging for Non-Invasive Pharmacokinetic Assessment of Chemotherapeutic Agents:

2. Physiologic Imaging/Tissue Oxygenation/Blood Flow

3. Contrast Enhancing Agents/Vascular Permeability

Several new MR imaging techniques have recently been developed that yield physiologic information in addition to high resolution anatomical detail. These techniques have been termed "functional MR" (fMR) and include localized spectroscopy, chemical shift imaging, MR angiography, perfusion and diffusion imaging, pharmacologic imaging and blood-oxygenation-level-dependent imaging. Contrast mechanisms originate from the magnetic susceptibility of hemoglobin, which is dependent upon its oxygenation state. Oxyhemoglobin (HbO2) is diamagnetic while deoxyhemoglobin (deoxy-Hb) is paramagnetic. The magnetic susceptibility difference between deoxy-Hb and surrounding tissue water creates local field gradients that cause phase dispersion of nearby water protons result in a loss of MR signal intensity.

This is important since metabolically activated tissue results in an increase in blood flow/blood volume to the specific area of activation. Excess arterial Hb-O2 then mixes with deoxy-Hb resulting in a net elevation of Hb-O2 in nearby veins and capillary beds. This yields in a net increase of MR signal intensity for metabolically active tissue using T2 and T2* weighted MR data acquisitions. However, since the resultant MR signal intensity changes are relatively small, special image processing techniques are required to extract the information from the raw data in order to directly visualize metabolically activated tissue.

Moreover, because this process is altered in diseased states, fMR imaging techniques are being increasingly investigated as a non-invasive tool to detect and assess changes in blood oxygenation and flow associated with pathophysiology such as acute stroke and ischemia. Our lab has pioneered this approach for studying changes in the hemodynamic status of tumors. Current experiments in our lab emphasize continued development of this fMR method for elucidating improved biochemical information concerning tumor physiology before and after treatment. Data are obtained from clinical diagnostic and research examinations as well as from small animal models of disease unique to RPCIC and SUNY at Buffalo researchers collaborating with this laboratory. Results are used to improve clinical diagnostic protocols, determine the angiogenic status and metastatic potential, and, for assessing the efficacy of new chemotherapeutic drugs.

Progress

Physiologic Imaging/Tissue Oxygenation/Blood Flow

Dr. Mazurchuk in collaboration with researchers at RPCIC, SUNY at Buffalo and elsewhere (Straubinger, Plunkett, Glaves-Rapp, Raghavan, Bernacki, Rustum) continues to develop customized techniques for assessing tumor response after treatment using several animal models of disease. Animal models currently in use include: rat 9L gliosarcoma, murine C26 colon carcinoma, human glioma implanted in the brain of nude rats, human bladder cancer in nude mice (implanted s.c. and in bladder wall), liver metastasis using human HT29 colon carcinoma in nude mice and Ward colon carcinoma in rat.

Dr. Mazurchuk in collaboration with Drs. Grossman and Klippenstein are using functional magnetic resonance imaging techniques (fMRI) to characterize regions of active tumor growth as a function of time and treatment. Regions within and adjacent to tumor (as demonstrated using standard contrast enhancing agents) are studied to assess blood flow, perfusion and oxygenation using non-invasive techniques. This work is performed in IRB approved clinical research evaluations and using animal models of disease. Perfusion weighted MR imaging has been purchased and initiated to study tumor hemodynamics as a function of treatment.

Dr. Mazurchuk in conjunction with Drs. Klippenstein, Gross, McGarry, Corral, Lohr, Duax, Noble, Hauptman, Burkhart, Griffin and other area leaders (Wilson Greatbatch, Clem Arrison) have formed the Polycystic Kidney Disease (PKD) Research Group of Western New York. This group meets monthly at the Hauptman-Woodward Medical Research Institute to discuss topics and areas of overlap concerning PKD research currently ongoing or planned in area laboratories.

Contrast Enhancing Agents/Vascular Permeability

Dr. Mazurchuk in collaboration with Drs. Grossman, Klippenstein, Alberico, Pandey and Lamonica continues to participate in a Multi-Disciplinary Contrast Agent Development group. Several model compounds are actively being designed, synthesized and tested as novel agents for perfusion imaging and brain tumor MR imaging using new tumor specific complexes. Several prototype formulations are currently being tested.

Dr. Mazurchuk in collaboration with Dr. Ziv (SUNY at Buffalo, Dept. of Orthopaedics) have developed a non-invasive technique to characterize changes in relative water distributions in intervertebral discs as a function of age in sand rats. Current efforts are aimed at monitoring similar changes in Sprague-Dawley rats induced by water intake and diet and to determine if suitable treatments to reverse the observed effects are possible.

Publications:

 

Activity of the Vascular-Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid against Human Head and Neck Carcinoma Xenografts  Mukund Seshadri, Richard Mazurchuk, Joseph A. Spernyak, Arup Bhattacharya,Youcef M. Rustum and David A. Bellnier Neoplasia Vol. 8, No. 7, July 2006, pp. 534 – 542

High Correlation of Whole-Body Red Fluorescent Protein Imaging and Magnetic Resonance Imaging on an Orthotopic Model of Pancreatic Cancer.  Michael Bouvet, Joseph Spernyak, Matthew H. Katz, Richard V. Mazurchuk, Shinako Takimoto, Ralph Bernacki, Youcef M. Rustum, Abdool R. Moossa and Robert M. Hoffman Cancer Res. 2005 Nov 1;65(21):9829-33.

Tumor vascular response to photodynamic therapy and the antivascular agent 5,6-dimethylxanthenone-4-acetic acid: implications for combination therapy. Seshadri M, Spernyak JA, Mazurchuk R, Camacho SH, Oseroff AR, Cheney RT, Bellnier DA. Clin Cancer Res. 2005 Jun 1;11(11):4241-50.

Magnetic resonance imaging of tumor response to chemotherapy. Mazurchuk R, Spernyak JA. Methods Mol Med. 2005;111:381-415.

Chlorophyll-a analogues conjugated with aminobenzyl-DTPA as potential bifunctional agents for magnetic resonance imaging and photodynamic therapy. Li G, Slansky A, Dobhal MP, Goswami LN, Graham A, Chen Y, Kanter P, Alberico RA, Spernyak J, Morgan J, Mazurchuk R, Oseroff A, Grossman Z, Pandey RK Bioconjug Chem. 2005 Jan-Feb;16(1):32-42.

Ventricular size mapping in a transgenic model of schizophrenia. Torres G, Meeder BA, Hallas BH, Spernyak JA, Mazurchuk R, Jones C, Gross KW, Horowitz JM.Brain Res Dev Brain Res. 2005 Jan 1;154(1):35-44.

Lack of microvessels in well-differentiated regions of human head and neck squamous cell carcinoma A253 associated with functional magnetic resonance imaging detectable hypoxia, limited drug delivery, and resistance to irinotecan therapy. Bhattacharya A, Toth K, Mazurchuk R, Spernyak JA, Slocum HK, Pendyala L, Azrak R, Cao S, Durrani FA, Rustum YM. Clin Cancer Res. 2004 Dec 1;10(23):8005-17.

Activated polyamine catabolism depletes acetyl-CoA pools and suppresses prostate tumor growth in TRAMP mice. Kee K, Foster BA, Merali S, Kramer DL, Hensen ML, Diegelman P, Kisiel N, Vujcic S, Mazurchuk RV, Porter CW. J Biol Chem. 2004 Sep 17;279(38):40076-83. Epub 2004 Jul 13.

Antivascular and antitumor activities of liposome-associated drugs. Straubinger RM, Arnold RD, Zhou R, Mazurchuk R, Slack JE. Anticancer Res. 2004 Mar-Apr;24(2A):397-404.

High-resolution magnetic resonance imaging of the efficacy of the cytosine analogue 1-[2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl]-N(4)-palmitoyl cytosine (CS-682) in a liver-metastasis athymic nude mouse model. Wu M, Mazurchuk R, Chaudhary ND, Spernyak J, Veith J, Pera P, Greco W, Hoffman RM, Kobayashi T, Bernacki RJ Cancer Res. 2003 May 15;63(10):2477-82

Antivasculature effects of doxorubicin-containing liposomes in an intracranial rat brain tumor model. Zhou R, Mazurchuk R, Straubinger RM. Cancer Res. 2002 May 1;62(9):2561-6

Magnetic resonance imaging of dense and light non-aqueous phase liquid in a rock fracture. Becker, M., Pelc, M., Mazurchuk, R., and Spernyak, J., Geophys. Res. Lett., 30(12), 1646

Mazurchuk, R., Glaves-Rapp, D., Raghavan, D., Magnetic resonance imaging of response to chemotherapy in orthotopic xenografts of human bladder cancer. Clin. Res. 3:1635-1641, 1997.

Mazurchuk R, Zhou R, Straubinger R, Grossman Z. Functional magnetic resonance (fMR) imaging of a rat brain tumor model: Implications for evaluation of tumor microvasculature and therapeutic response. Mag. Res. Imaging 17:537-548, 1999.

Matwiyoff NA, Gasparovic C, Mazurchuk, R, Matwiyoff G. The line shapes of the water proton resonances of red blood cells containing carbonyl hemoglobin, deoxyhemoglobin, and methemoglobin: Implications for the interpretation of proton MRI at fields of 1.5 T and below. Mag. Res. Imaging 8:295-301, 1990.

Matwiyoff NA, Gasparovic C, Mazurchuk R. On the origin of paramagnetic in homogeniety effects in whole blood. Mag. Res. in Med. 20:144-150, 1991.