Center for Anticancer Drug Research
Center for Anticancer Drug Research
Mission
The mission of the Center for Anticancer Drug Research is to
improve the chemotherapeutic treatment of cancer through the development of
novel compounds that eradicate chemoresistant tumor cells, while reducing
life-threatening, adverse effects.
Dept. of Pharmacology |
Dept. of Physiology |
Mervyn Israel, Ph.D. |
Polly A. Hofmann, Ph.D |
Leonard Lothstein, Ph.D. |
Dept. of Medicine (Cardiology) |
D. Parker Suttle, Ph.D. |
Judith E. Soberman, M.D. |
Trevor W. Sweatman, Ph.D. |
Dept. of Comparative Medicine |
|
|
Timothy Mandrell, D.V.M., Chair |
The Center for Anticancer Drug Research (CADR) is an appellation giving to an already longstanding and highly productive collaboration among eight faculty members of the University of Tennessee College of Medicine faculty. The members of CADR share a common interest in anticancer drug design, mechanistic analysis and therapeutic implementation, particularly of anthracycline compounds. Although CADR member demonstrate diverse areas of expertise, ranging from organic synthesis to molecular biology to cardiovascular pharmacology, this has proven to be a highly complementary arrangement in the development and analysis of anthracycline congeners that have improved antitumor efficacy through increased cytotoxicity, circumvention cellular drug resistance and the significant reduction of cardiological adverse effects.
As a medicinal chemist, Dr. Mervyn Israel has synthesized an extensive array of semisynthetic anthracyclines both as a member of the Dana-Farber Cancer Institute in Boston and for the last 20 years on the faculty of the Department of Pharmacology at the University of Tennessee Health Science Center (UTHSC). These efforts have resulted in the development of several atypical anthracyclines whose mechanisms of action have recently be shown to be distinct from typical nuclear-targeted anthracyclines such as doxorubicin or daunorubicin. Among this class of compounds are N-benzyladriamycin-14-valerate (AD 198), a patented compound (M. Israel/UT Research Corp.) that appears to circumvent all known clinically relevant mechanisms of drug resistance and is non-cardiotoxic, and N-trifluoroacetyladriamycin-14-valerate (AD 32/Valrubicin/Valstar®), which is currently FDA-approved for bladder tumors as a chemotherapeutic alternative to systectomy.
Joining Dr. Israel in these efforts at both Dana-Farber and UTHSC is Dr. Trevor Sweatman, whose pharmacokinetic expertise has provided an understanding of in vivo anthracycline distribution and metabolism. Further, Dr. Sweatman’s investigations in AD 198 and protein kinase C interactions have led to the identification of this essential signaling enzyme as a target for AD 198 and other closely related anthracyclines.
Further studies in collaboration with Dr. Parker Suttle, who join the Dept. of Pharmacology from St. Jude Children’s Research Hospital with expertise in drug/topoisomerase II interaction, resulted in the identification of novel semisynthetic anthracyclines that functioned as catalytic inhibitors of topoisomerase II.
Recently initiated investigations include the characterization of potential
cardioprotective effects of AD 198 in collaboration with Dr. Polly Hofmann
of the Dept. of Physiology (UTHSC), Dr. Judith Soberman (Dept. of Medicine,
UTHSC) and Dr. Tim Mandrell (Dept. of Comparative Medicine, UTHSC) and the
interaction of Nf-kB and p53 transcriptional factors on the cytotoxicity of
conventional and atypical anthracyclines through a collaboration with Dr.
Marcello Arsura, who joined the Dept. of Pharmacology faculty in 2000 from
Boston University.
Resources for the CADR encompass the laboratory space allocated to each center member by the University of Tennessee Health Science Center. This includes approximately 4,000 sq. ft. of laboratory and office space within the Department of Pharmacology, approximately 2,500 sq. ft. within the Department of Physiology and access to 38,000 sq. ft. of animal space comprising the Department of Comparative Medicine located in 4 buildings on the Memphis campus. The entire centralized animal care program is fully accredited by the Association for Accreditation and Assessment of Laboratory Animal Care, International (AAALAC) and maintains an Animal Welfare Assurance with the NIH Office of Laboratory Animal Welfare (OLAW).
The following pieces of major equipment are located within the laboratories
of the members of the CADR:
Biochemistry/Molecular Biology: Perkin Elmer UV/VIS spectrophotometer and
data station, thermal cyclers for PCR, Savant "speed-vac" concentrator,
Bioscan QC2000 beta/gamma counter, minifluorometer for small quantity DNA
quantification, lyophilyzer, -80°C freezer, walk-in cold room, various
clinical, medium-speed and high-speed (ultra) centrifuges, automated X-ray
film developer.
Cell Culture: Adenovirus production facility, 8 Water-jacketed CO2 incubators,
5 cell culture hoods, liquid nitrogen storage facility, 2 Coulter cell counters,
microtiter plate reader for drug toxicity assays, Nikon phase-contrast epifluorescence
microscope, inverted photomicroscope, water deionization unit.
Organic Chemistry: Waters fluorescence HPLC systems with computer-driven
flow fluorimeters, automated wisp sampler, photodiode array detector for drug
purity determinations and intracellular drug analyses, infrared spectrometer,
mass spectrograph.
Cardiological Analysis: Two experimental set-ups used for mechanical measurements
of single myocytes [Nikon inverted microscope with photographic attachments,
experimental chamber, vibration isolation table, X-Y recorder, piezoelectric
translator with power supply (KEPCO, BOP 1000M), force transducer (Cambridge
403), and 2 Narishigi positioners], two experimental set-ups to measure isolated
rat and mouse heart mechanics [pressure transducer, temperature controlled
Langendorff perfusion apparatus with organ bath, pacing equipment, and O2-CO2
delivery system]. All set-ups include interfaces with Macintosh computer systems
for the control of the experiments and recording of data.
Animal Research Resources: The Department of Comparative Medicine maintains
specialized surgical, diagnostic, and research equipment for large animal
research. DCM maintains two modern surgical suites with state of the art surgical,
anesthesia, and monitoring equipment. Equipment available to support this
project includes a Hewlett Packard 2000 echocardiographic system, MacLab 8e
data acquisition system, two Hewlett Packard multi-channel monitors (78534A
and 78354A), and an OEC DXR 5 C-arm fluoroscope, centrifuges, and a Forma-Scientific
ultra-low freezer.
Funding
Active
Susan G. Komen Foundation for Breast Cancer Research Basic Research Award
BCTR 99-3307 (12/01/99-5/15/02): “Circumvention of Bcl-2 Apoptotic Inhibition
by 14-O-Acyl Anthracyclines”; Principal Investigator, L. Lothstein. Total
direct costs, $193,221.
NIH/NCI 1RO1 CA 78616 (02/01/99-01/31/04): “Role of NF-kB in TGF-b1-induced Apoptosis of Hepatocytes” . Principal Investigator, M. Arsura. Total direct costs, $159,257.
NIH/NHLBI RO1 HL48839-09 (2001-2006): Mechanisms of Hormonal Regulation of
Cardiac Contraction”, Principal Investigator, PA Hofmann. Total direct
costs, $875,000.
Pending
NIH/NC1 RO1 (2002-05): “Apoptotic Signaling by 14-O-Acylanthracyclines”.
Principal Investigator, L. Lothstein; Co-Investigators, T.W. Sweatman, M.
Israel. Total direct costs, $675,000.
NIH/NHLBI (2001-05): “Cardioprotection by 14-O-Acylanthracycline Protein
Kinase C Modulators”. Principal Investigator, L. Lothstein; Co-Investigators,
P.A. Hofmann, T.W. Sweatman, J.E. Soberman, T. Mandrell. Total direct costs,
$875,000.
NIH/NCI RO1 (2002-06): “Novel C1b Modulation of PKC by 14-Acylanthracyclines”.
Principal Investigator, T.W. Sweatman; Co-Investigators, L. Lothstein, M.
Israel. Total direct costs, $1,014,614.
American Heart Association Grant-in-Aid (2002-04): “Cardioprotection
by 14-O-Acylanthracycline Protein Kinase C Modulators”. Principal Investigator,
L. Lothstein; Co-Investigators, P. Hofmann, T.W. Sweatman, M. Arsura. Total
direct costs, $200,000.
Publications
1. Wang Q, Zambetti GP, Suttle DP. Inhibition of DNA topoisomerase IIa gene
expression by the p53 tumor suppressor. Mol. Cell. Biol. 17: 389-397,1997.
2. Greenberg RE, Bahnson, RR, Wood D, Childs, SJ, Bellingham C, Edson C, Bamberger MH, Steinberg, GD, Israel M, Sweatman TW, Giantonio B, O’Dwyer PJ. Initial report on intravesical administration of N-trifluoroacetyladriamycin-14-valerate (AD 32) to patients with refractory superficial transitional carcinoma of the urinary bladder. Urology 49: 471-475, 1997.
3. Ying G-G, Arsura M, Introna M, Golay J. The DNA binding domain of the A-myb transcription factor is responsible for its B cell specificity and binds to a B cell 110 kD nuclear protein. J.Biol.Chem. 272:1-6,1997.
4. Arsura M, Fitzgerald MJ, Fausto N, Sonenshein GE. NF-kB/Rel blocks transforming growth factor-b1-induced apoptosis of murine hepatocyte cell lines. Cell Growth Diff. 8: 1049-1059, 1997.
5. Wu M, Yang W, Bellas RE, Schauer SL, Arsura M, Lee H, FitzGerald MJ, Sonenshein GE. c-Myc promotes survival of WEHI 231 B lymphoma cells from apoptosis. Current Topics in Micro. Immunol. 224, 91-101,1997.
6. Marhamati DJ, Bellas RE, Arsura M, Kypreos KE, Sonenshein GE. A-myb is expressed in bovine vascular smooth muscle cells during the late G1/S phase transition and cooperates with c-myc to mediate progression to S phase. Mol. Cell Biol. 17: 2448-2457,1997.
7. Berry MJ, Brubaker PH, O’Toole ML, Rejeski WJ, Soberman J. Estimation of VO2 in older individuals with osteoarthritis of the knee and cardiovascular disease. Med Sci. Sports. Exer. 28: 808-814, 1997.
8. Lampidis TJ, Kolonias D, Podona T, Israel M, Safa AR, Lothstein L, Savaraj N, Tapiero H, and Priebe W. Circumvention of P-gp MDR as a function of anthracycline lipophilicity and charge. Biochemistry 36: 2679-2685, 1997.
9. Li P, Hofmann PA, Li B, Malhotra A, Cheng W, Sonnenblick EH, Meggs LG, Anversa P. Myocardial infarction alters myofilament calcium sensitivity and mechanical behavior of myocytes. Am. J. Physiol. 272: H360-370, 1997.
10. Lothstein L, Rodrigues PJ, Sweatman TW, Israel M. Intracellular activity, distribution, and metabolism of N-Benzyladriamycin-14-valerate (AD 198) are modulated by changes in 14-O-acyl chain length. Anti-Cancer Drugs 9: 8-16, 1998.
11. Parker SL., Parker MS, Sweatman TW, Crowley WR. Charecterization of G-protein and phospholipase C-coupled agonist binding to the Y1 neuropeptide Y receptor in rat brain. J. Pharm. Exp. Therap. 286: 382-388, 1998.
12. Pawlik CA, Sweatman T, Israel M, Lothstein L. Multifactorial resistance to the novel hybrid drug 2-chloroethyl-nitrosoureidodaunorubicin (AD 312) in murine and human tumor cells. Oncology Res. 10: 209-218, 1998.
13. Rigby SL, Hofmann PA, Zhong J, Adams HR, Rubin LJ. Endotoxemia-induced myocardial dysfunction is not associated with changes in myofilament Ca2+ responsiveness. Am. J. Physiol. 274: H580-590, 1998.
14. Redaelli G, Malhotra A, Li B, Li P, Sonnenblick EH, Hofmann PA, Anversa P. Effects of constitutive overexpression of insulin-like growth factor-1 on the mechanical characteristics and molecular properties of ventricular myocytes. Circ. Res. 82: 594-603, 1998.
15. Torchinsky C, Messana EP, Arsura M, Cotanche DA. Regulation of p27Kip1 during gentamicin mediated hair cell death. J. Neurocytol. 28: 913-924,1999.
16. Fitzgerald MJ, Arsura M, Wu M, Chin L, Mann KK, Depinho RA, Sherr DH, Sonenshein GE. The widely expressed dMax splice variant of Max associates with Max binding partners and inhibits c-Myc functions in vitro, and induces apoptosis in the WEHI 231 murine B cell line. Oncogene 18: 2489-2498, 1999.
17. Sovak MA, Arsura M, Zanieski G, Kavanagh KT, Sonenshein GE. The inhibitory effects of transforming growth factor-b1 on breast cancer cell proliferation are mediated through regulation of aberrant nuclear factor-kB/Rel expression. Cell Growth Diff. 10: 537-544,1999.
18. Chen G, Templeton D, Suttle DP, Stacy DW. Ras stimulates DNA topoisomerase IIa through MEK: A link between oncogenic signaling and a therapeutic target. Oncogene 18: 7149-7160, 1999.
19. Hoye WE, Soberman JE, Walters G. Neuropsychological consultation in medical decision making: anosodiaphoria and neglect following embolic infarction associated with bacterial endocarditis. Archives of Clinical Neuropsychology 14: 132-133, 1999.
20. Sweatman, TW, Seshadri R, Israel M. Pharmacology of N-benzyladriamycin-14-valerate (AD 198) in the rat. Cancer Chemotherap. Pharmacol., 4: 419-426, 1999.
21. Chafin CC, Soberman JE, Demirkan K, Self T. Beta-blockers after myocardial infarction: Do benefits ever outweigh risks in asthma? Cardiology 92: 99-105, 1999.
22. Arsura M, Hofmann CS, Golay J, Introna M, Sonenshein GE. A-myb rescues murine B cell lymphomas from IgM-receptor-mediated apoptosis through c-myc transcriptional regulation. Blood 96: 1013-1020, 2000.
23. Arsura M, Mercurio F, Oliver AL, Thorgeirsson SS, Sonenshein GE. Role of IkappaB kinase complex in oncogenic ras- and raf-mediated transformation of rat liver epithelial cells. Mol. Cell. Biol. 20: 5381-5391, 2000.
24. Arsura M, Sonenshein GE. The role of c-myc and c-myb oncogenes in hematopoiesis and leukemogenesis. In: Transcription factors: normal and malignant development of blood cells. (K. Ravid and J. Licht editors). John Wiley and Sons, Inc., 2000.
25. Soberman, JE, Wever KT. Spironolactone in congestive heart failure. Current Hypertension Reports 2: 451-454, 2000.
26. Demirkan K, Tolley E, Mastin T, Soberman JE, Burbeck J, Self T. Salmeterol administration by metered dose inhaler (MDI) alone vs. MDI plus spacer device. Chest 117, 2000.
27. Wani MK, Koseki Y, Yarber RH, Sweatman TW, Ahmed A, Samant S, Hengesteg A, Israel M, Robbins, KT. Rationale for intralesional valrubicin in chemoradiation of squamous carcinoma of the head and neck. Laryngoscope 110: 2026-2032, 2000.
28. Patterson AL, Greenberg RE, Weems L, Bahnson R, Wajsman Z, Israel M, Sweatman T, Webber D, Gulfo J. Pilot study of the tolerability and toxicity of intravesical valrubicin immediately after transurethral resection of superficial bladder cancer. Urology 56: 232-235, 2000.
29. Oliver FM, Sweatman TW, Unkel JH, Kahn MA, Randolph MM, Arheart KL, Mandrell TD. Comparative pharmacokinetics of submucosal vs. intravenous flumazenil (Romazicon) in an animal model. Pediatr. Dent. 22: 489-493, 2000.
30. Self T, Chafin CC, Soberman J. Effect of disease states on the theophylline serum concentrations: Are we still vigilant. Am. J. Med. Sci. 319: 177-182, 2000.
31. Joshi AA, Wang Q, Suttle DP. p53 Modulation of DNA Topoisomerase IIa Gene Expression. Cell Biochem. Biophys. 33: 209-216, 2000.
32. Lothstein L, Suttle DP, Roaten JR, Koseki Y, Israel M, Sweatman TW. Catalytic inhibition of topoisomerase II by N-Benzyladriamycin (AD 288). Biochem. Pharmacol. 60: 1621-1628, 2000.
33. Pyle WG, Smith TD, Hofmann PA. Cardioprotection with kappa-opioid receptor stimulation is associated with a slowing of cross-bridge cycling. Am. J. Physiol. Heart Circ. Physiol. 279: H1941-1948, 2000.
34. Factor V, Oliver AL, Panta G, Thorgeirsson SS, Sonenshein GE, Arsura M. Roles of Akt/PKBand IKK complex in constitutive induction of NF-kB in hepatocellular carcinomas of TGF-a/c-myc transgenic mice. Hepatology 34: 32-41, 2001.
35. Yang W, Shen J, Wu M, Arsura M, Fitzgerald M, Suldan Z, Kim DW, Hofmann CS, Pianetti S, Romieu-Mourez R, Freedman LP, Sonenshein GE. Repression of transcription of the p27 Kip1 cyclin-dependent kinase inhibitor gene by c-Myc. Oncogene 20: 1688-1702, 2001.
36. Pianetti S, Arsura M, Romieu-Mourez R, Coffey RJ, Sonenshein GE. Her-2/neu overexpression induces NF-kB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IkB-a that can be inhibited by the tumor suppressor PTEN. Oncogene 20: 1287-1299, 2001.
37. Lester JW, Hofmann PA. Role for PKC in the adenosine-induced decrease in shortening velocity of rat ventricular myocytes. Am. J. Physiol. Heart. Circ. Physiol. 279: H2685-2693, 2000.
38. Roaten JB, Kazanietz MG, Sweatman, TW, Lothstein L, Israel M, Parrill AL. Molecular Models of N-Benzyladriamycin-14-valerate (AD 198) in complex with the phorbol ester-binding C1b domain of protein kinase C-d. J. Med. Chem. 44: 1028-1034, 2001.
39. Pyle WG, Lester JW, Hofmann PA. Effects of kappa-opioid receptor activation on myocardium. Am. J. Physiol. Heart. Circ. Physiol. 281: H669-678, 2001.
40. Lothstein L, Israel M, Sweatman TW. Anthracycline targeting: Nuclear versus cytoplasmic-A fork in the road (Invited Review) Drug Resistance Updates. 2001 In Press.
41. Roaten JB, Kazanietz MG, Caloca MJ, Bertics PJ, Wiepz GJ, Parrill AL, Rodrigues PJ, Lothstein L, Israel M, Sweatman TW. Protein kinase C inhibition by N-benzyladriamycin-14-valerate (AD 198): Structural requirements, isoform specificity and interaction with the C1-regulatory domain. Cancer Research, Submitted.
42. Barrett CM, Roaten JB, Lewis FL, Sweatman TW, Israel M, Lothstein L. Modulation of protein kinase C (PKC) activity correlates with circumvention of Bcl-2-mediated inhibition of apoptosis by N-benzyladriamycin-14-valerate (AD 198). Cancer Research, Submitted.
43. Joshi AA, Wu Z, Reed RF, Suttle DP. NF-Y binding of the topoisomerase IIa promoter is inhibited by both the p53 tumor suppressor and anticancer drugs. Submitted.
44. Lothstein L, Barrett CM, Savranskaya, L. Direct correlation of N-benzyladriamycin-14-valerate (AD 198) cytotoxicity to protein kinase C-a levels in pig renal epithelial cells. In preparation.
45. Lothstein L, Sweatman TW, Priebe, W. Mechanism of Action of 14-O-acyl analogs of hydroxyrubicin (WP159). In preparation