Janet Houghton Ph.D.

Staff

  • Department of Cancer Biology
  • Lerner Research Institute
  • 9500 Euclid Avenue
  • Cleveland, Ohio 44195
  • houghtj@ccf.org
  • Phone: (216) 445-9652
  • Fax: (216) 445-6269

Colorectal cancer is the third leading cause of cancer deaths in the United States, underscoring the critical need for new discoveries in tumor biology, new targets for the development of anti-cancer agents, and new innovative treatment approaches.  We have demonstrated that aberrant signaling via the Hedgehog (HH) pathway is critical to the survival of colon cancer cells, contributing significantly to genomic instability, oncogenesis, progression and metastasis. Canonical HH signaling engages the transmembrane receptor PTCH, the signaling molecule SMO, and the transcriptional regulators of HH target genes, GLI1 and GLI2. We have demonstrated in colon cancer that oncogene-driven signaling pathways, specifically KRAS/BRAF, aberrantly converge on and activate GLI genes, integrating at the level of GLI2, and circumvent the HH-SMO axis. GANT61, a small molecule inhibitor of GLI1/GLI2 transcription, induces extensive cell death in human colon carcinoma cell lines in contrast to targeting SMO, thereby terminating KRAS/BRAF signaling, and delineating GLI as a critical target. During prolonged GANT61 exposure, GLI1, GLI2 and target gene promoters are coordinately regulated by H3K9 methylation to promote gene silencing and reduction in cell cycle transition at G1/S, delineating a unique mechanism to avoid cell death from GLI targeting.  How GLI and GLI2 are regulated in normal cells or in cancer cells remains poorly understood, yet GLI marks an important target in tumor biology and for drug development. These approaches will provide new insight into critical targets that determine HH-dependent survival, and to translation of agents that target GLI.

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  • Akwasi Agyeman Ph.D.
  • Research Fellow
  • Location:NB4-125
  • Phone:(216) 445-9653
  • Fax:(216) 445-6269
  • agyemaa@ccf.org

ORIGINAL RESEEARCH ARTICLES

Houghton PJ, Houghton JA, Taylor DM. Effects of cytotoxic agents on TdR incorporation and growth delay in human colonic tumour xenografts. Br J Cancer 36:206-214, 1977.

Houghton JA, Taylor DM. Maintenance of biological and biochemical characteristics of human colorectal tumours during serial passage in immune-deprived mice. Br J Cancer 37:199- 212, 1978.

Houghton JA, Taylor DM. Growth characteristics of human colorectal tumours during serial passage in immune-deprived mice.Br J Cancer 37: 213-223, 1978.

Reeves BR, Houghton JA. Serial cytogenetic  studies  of  human  colonic tumour xenografts. Br J Cancer 37:612-619, 1978.

Houghton PJ, Houghton JA. Evaluation of single-agent-therapy in human colorectal tumour xenografts. Br J Cancer 37:833-840, 1978.

Houghton JA, Houghton PJ. Evaluation of cytotoxic agents in human colonic tumor xenografts and mouse gastrointestinal tissue using  3H-thymidine  fractional  incorporation  into DNA. Eur J Cancer 15:763-769, 1979.

Houghton JA, Houghton PJ, Wooten RS. Mechanism of induction  of gastrointestinal toxicity in the mouse by 5-fluorouracil, 5-fluorouridine and 5-fluoro-2'-deoxyuridine. Cancer Res 39:2406-2413,  1979.

Houghton JA, Houghton PJ. On the mechanism of cytotoxicity of fluorinated pyrimidines in four human colon adenocarcinoma xenografts maintained in immune-deprived mice. Cancer 45:1159-1167, 1980.

Houghton JA, Houghton PJ. 5-fluorouracil in combination  with hypoxanthine  and allopurinol: Toxicity and metabolism in xenografts of human colonic carcinomas in mice. Biochem Pharmacol 29:2077-2080, 1980.

Houghton JA, Maroda SJ, Phillips JO, Houghton PJ. Biochemical determinants of responsiveness to 5-fluorouracil and its derivatives in human colorectal adenocarcinoma xenografts. Cancer Res 44:144-149, 1981.

Houghton JA, Houghton PJ, Brodeur GM, Green AA. Development of resistance to vincristine in a childhood rhabdomyosarcoma growing in immune-deprived mice. Int J Cancer 28:409-415, 1981.

Houghton JA, Houghton PJ, Green AA. Chemotherapy of  childhood rhabdomyosarcomas growing as xenografts in immune-deprived mice. Cancer Res 42:535-539, 1982.

Houghton JA, Houghton PJ, Webber BL. Growth and characterization of childhood rhabdomyosarcomas as xenografts.  J Natl Cancer Inst 68:437-443, 1982.

Houghton JA, Schmidt C, Houghton PJ. The effect of derivatives of folic acid on the fluorodeoxyuridylate-thymidylate synthetase covalent complex in human colon xenografts. Eur J Cancer Clin Oncol 18:347-354, 1982.

Houghton JA, Houghton PJ. Combinations of 5-fluorouracil, hypoxanthine and allopurinol in the chemotherapy of human colon adenocarcinoma xenografts. Cancer Treat Rep 66:1201- 1206, 1982.

Houghton JA, Tice AJ, Houghton PJ. The selectivity of action of methotrexate in combination with 5-fluorouracil  in xenografts of  human colorectal  adenocarcinomas.  Mol Pharmacol 22:771-778, 1982.

Houghton PJ, Houghton JA. Chemotherapeutic response in xenografts: inter- and intra- tumor heterogeneity. In: Chabner BA, ed. Rational Basis for Chemotherapy. New York: Alan R. Liss, pp. 61-69, 1983.

Houghton JA, Houghton PJ. Elucidation of pathways of 5-fluorouracil metabolism in xenografts of human colorectal adenocarcinomas. Eur J Cancer Clin Oncol 19:807-815, 1983.

Houghton JA, Torrance PM, Houghton PJ. Chromatographic analysis of Vinca alkaloids in human neoplastic tissues and host (mouse) tissues after injection in vivo, or after incubation in vitro. Anal Biochem 134:450-454, 1983.

Houghton JA, Williams LG, Torrance PM, Houghton PJ. Determinants of intrinsic sensitivity to Vinca alkaloids in xenografts of pediatric rhabdomyosarcomas. Cancer Res 44:582-590, 1984.

Houghton JA, Cook RL, Lutz PJ, Houghton  PJ.  Childhood rhabdomyo-sarcoma xenografts: Response to DNA interacting agents used in current clinical therapy. Eur J Cancer Clin Oncol 20:955-960, 1984.

Houghton JA, Houghton PJ. Basis for the interaction of 5-fluorouracil and leucovorin in colon adenocarcinoma. In: Bruckner HW, Rustum YM, eds. Advances in Cancer Chemotherapy. Park Row Publishers, pp. 23-32, 1984.

Houghton JA, Cook RL, Lutz PJ, Houghton PJ. Melphalan: a potential new agent in the treatment of childhood rhabdomyosarcoma. Cancer Treat Rep 69:91-96, 1985.

Mullin K, Houghton PJ, Houghton JA, Horowitz ME. Studies with 4'-deoxyepivincristine (Vinepidine), a semisynthetic Vinca alkaloid. Biochem Pharmacol 34:1975-1979, 1985.

Houghton JA, Houghton PJ, Hazelton BJ, Douglass EC. In situ selection of a human rhabdomyosarcoma resistant to  vincristine  with  altered  b-tubulins. Cancer Res 45:2706-2712, 1985.

Brent TP, Houghton PJ, Houghton JA. O6-Alkylguanine-DNA alkyltransferase activity correlates with the therapeutic response of human rhabdomyosarcoma xenografts to MeCCNU. Proc Natl Acad Sci USA 82:2985-2989, 1985.

Houghton JA, Williams LG, Houghton PJ. Stability of vincristine complexes in cytosols derived from xenografts of human rhabdomyosarcoma and normal tissues of  the  mouse. Cancer Res 45:3761-3767, 1985.

Houghton JA, Weiss KD, Williams LG, Torrance PM, Houghton PJ. The relationship between 5-fluoro-2'-deoxyuridylate, 2'-deoxyuridylate, and thymidylate  synthase  activity subsequent to 5-fluorouracil administration in xenografts of human colon adenocarcinomas. Biochem Pharmacol 35:1351-1358, 1986.

Houghton JA, Torrance PM, Radparvar S, Williams LG, Houghton PJ. Binding of 5- fluorodeoxyuridylate to thymidylate synthase in human colon adenocarcinoma xenografts. Eur J Cancer Clin Oncol 22:505-510, 1986.

Bowman LC, Houghton JA, Houghton PJ. GTP influences the binding of vincristine in human tumor cytosols. Biochem Biophys Res Commun 135:695-700, 1986.

Martin DS, Balis ME, Fisher B, Frei E, Freireich EJ, Heppner GH, Holland JF, Houghton JA, Houghton PJ, Johnson RK, Mittleman A, Rustum Y,  Sawyer RC,  Schmid  FA,  Stolfi  RL, Young CW. Role of murine tumor models in cancer treatment research. Cancer Res 46:2189- 2192, 1986.

Meyer WH, Houghton JA, Lutz PJ, Houghton PJ. Hypoxanthine: guanine phosphoribosyl transferase activity in xenografts of human osteosarcoma. Cancer Res 46:4896-4899, 1986.

Horowitz ME, Parham DM, Douglass EC, Kun LE, Houghton JA, Houghton PJ. Development and characterization of human ependymoma xenograft HxBR5. Cancer Res 47:499-504, 1987.

Houghton JA, Williams LG, Dodge RK, George SL, Houghton PJ. Relationship between binding affinity, retention and sensitivity of human rhabdomyosarcoma xenografts to Vinca alkaloids. Biochem Pharmacol 36:81-88, 1987.

Houghton JA, Radparvar S, Torrance PM, Williams LG, Houghton PJ. Determination of thymidylate synthase activity in colon tumor tissues after treatment with 5-fluorouracil. Biochem Pharmacol 36:1285-1289, 1987.

Meyer WH, Houghton JA, Houghton  PJ.  Hypoxanthine:guanine phosphoribosyltransferase activity in primary  human  osteosarcomas.  A rationale  for  therapy with methotrexate-thymidine rescue? J Clin Oncol 5:657-661, 1987.

Houghton PJ, Houghton JA, Germain G,  Torrance  PM.  Development and characterization of a human colon adenocarcinoma xenograft deficient in  thymidine  salvage. Cancer Res 47:2117-2122, 1987.

Houghton JA, Meyer WH,  Houghton  PJ.  Scheduling  of  vincristine: drug accumulation and response of xenografts of childhood rhabdomyo-sarcoma determined by frequency of administration. Cancer Treat Rep 71:717-721, 1987.

Hazelton BJ, Houghton JA, Parham DM, Douglass EC, Torrance PM, Holt H, Houghton PJ. Characterization of cell lines derived from xenografts of childhood  rhabdomyosarcoma. Cancer Res 47:4501-4507, 1987.

Houghton PJ, Houghton JA, Bowman LC, Hazelton BJ. Therapeutic selectivity of Vinca alkaloids: a role for guanosine 5'-triphosphate? Anticancer Drug Design 2:165-179, 1987.

Douglass EC, Valentine M, Etcubanas E, Parham D, Webber BL, Houghton PJ, Houghton JA, Green AA. A  specific  chromosomal  abnormality  in rhabdomyosarcoma. Cytogenet Cell Genet 45:148-155, 1987.

Radparvar S, Houghton PJ, Houghton JA. Characteristics of thymidylate synthase purified from a human colon adenocarcinoma. Arch Biochem Biophys 260:342-350, 1987.

Horton JK, Houghton PJ, Houghton JA. Reciprocal cross-resistance in human rhabdomyosarcomas selected in vivo for primary resistance to vincristine and L-phenylalanine mustard.  Cancer Res 47:6288-6293, 1987.

Horowitz ME, Etcubanas E, Christensen M, Houghton JA, George SL, Green AA, Houghton PJ. Phase II testing of melphalan in children with newly diagnosed rhabdomyosarcoma: a model for anticancer drug development.  J Clin Oncol 6:308-314, 1988.

Bowman LC, Houghton JA, Houghton PJ. Formation and stability of vincristine-tubulin complex in kidney cytosols: the role of GTP and GTP hydrolysis. Biochem Pharmacol 37:1251- 1257, 1988.

Houghton JA, Williams LG, Radparvar S, Houghton PJ. Characterization of the pools of 5,10-methylenetetrahydrofolates and tetrahydrofolates in xenografts of human colon adenocarcinoma.   Cancer Res 48:3062-3069, 1988.

Houghton PJ, Tharp R, Houghton JA, Bekesi GJ, Holland JF. Evaluation of 3-(p- fluorophenyl)-L-alanyl-3-[m-bis-(2-chloroethyl)aminophenyl]-L-alanyl-L-methionine    ethyl    ester HCl (PTT.119) against xenografts of human rhabdomyosarcoma. Cancer Chem Pharmacol 22:201-204, 1988.

Horton JK, Houghton PJ, Houghton JA. Relationship between tumor responsiveness, vincristine pharmacokinetics and arrest of mitosis in human tumor xenografts. Biochem Pharmacol 37:3995-4000, 1988.

Houghton JA, Williams LG, de Graaf SSN, Radparvar S, Wainer IW, Rodman JR, Houghton PJ. Selectivity of CF and 5-fluorouracil: critical role of polyglutamylation. In "The Expanding Role of Folates and Fluoropyrimidines in Cancer Chemotherapy".  Rustum  Y, McGuire JJ (eds), Plenum Publishing Corp., pp. 85-95, 1988.

Radparvar S, Houghton PJ, Houghton JA. Effect of polyglutamylation of 5,10- methylenetetrahydrofolate on the binding of 5-fluorodeoxyuridylate to thymidylate synthase purified from a human colon  adenocarcinoma  xenograft.  Biochem  Pharmacol  38:335-342, 1989.

Houghton PJ, Germain GS, Hazelton BJ, Pennington JW, Houghton  JA. Mutants  of human colon adenocarcinoma selected for thymidylate synthase deficiency. Proc Natl Acad Sci USA 86:1377-1381, 1989.

Houghton PJ, Houghton JA, Hazelton BJ, Radparvar  S.  Biochemical mechanisms  in colon xenografts: thymidylate synthase as  a  target  for therapy.  Invest  New  Drugs  7:59-69, 1989.

Horton JK, Thimmaiah KN, Houghton JA, Horowitz ME, Houghton PJ. Modulation by verapamil of vincristine pharmacokinetics and toxicity in mice bearing human tumor xenografts. Biochem Pharmacol 38:1727-1736, 1989.

Houghton JA, Williams LG, de Graaf SSN, Cheshire PJ, Wainer IW, Jadaud P, Houghton PJ. Comparison of the conversion of 5-formyltetrahydrofolate and 5- methyltetrahydrofolate to 5,10-methylenetetrahydrofolates and tetrahydrofolates in human colon tumors.  Cancer Commun 1:167-174, 1989.

Houghton PJ, Mirro J, Goorha R, Raimondi SM, Fridland A, Houghton JA. Metastatic growth and differentiation of a  T-cell  leukemia  grafted  in mice.  Cancer  Res  49:7124-7131, 1989.

Houghton PJ, Houghton JA, Myers L, Cheshire PJ, Howbert JJ, Grindey GB. Evaluation of  5-(indanylsulfonyl)-N'-(4-chlorophenyl)-urea  against xenografts  of  pediatric rhabdomyosarcoma.   Cancer Chemother Pharmacol 25:84-88, 1989.

Meyer WH, Houghton PJ, Horowitz ME, Etcubanas E, Pratt CB, Hayes FA, Thompson EI, Green AA, Houghton JA, Sandlund JT, Crist W. Use  of investigational  drugs  as  initial therapy for childhood solid tumors. In: Neth R, ed. Modern Trends in Human Leukemia. VIII. Berlin: Springer-Verlag, pp 141-148, 1989.

Houghton JA, Williams LG, Cheshire PJ, Houghton PJ, de Graaf SSN. Therapeutic strategies for 5-fluorouracil-leucovorin based upon cellular  metabolic characteristics in human colon adenocarcinoma xenografts. In: Proceedings of the 9th International Symposium on Pteridines and Folic Acid Derivatives. Zurich, Switzerland: Walter de Gruyter, pp 1203-1208, 1990

Houghton PJ, Bailey GC, Germain GS, Grindey GB, Howbert JJ, Houghton JA. Studies on the cellular pharmacology of N-(4-methylphenylsulfonyl)-N'-(4-chlorophenyl)-urea. Biochem Pharmacol 39:1187-1192, 1990.

Houghton PJ, Bailey FC, Germain GS, Grindey GB, Witt BC, Houghton JA. Cytotoxic activity of N-(5-indanylsulfonyl)-N'-(4-chlorophenyl)-urea: a novel agent equally cytotoxic to nonproliferating cells.  Cancer Res 50:318-322, 1990.

Houghton PJ, Bailey FC, Houghton JA, Murti KG, Howbert JJ, Grindey GB. Evidence for localization of N-(4-methylphenylsulfonyl)-N'-(4-chlorophenyl)-urea in mitochondria of colon adenocarcinoma cells. Cancer Res 50:664-668, 1990.

Radparvar S, Houghton PJ, Germain G, Pennington J, Rahman A, Houghton  JA. Cellular pharmacology of 5-fluorouracil in a human colon adenocarcinoma cell line selected for thymidine kinase deficiency. Biochem Pharmacol 39:1759-1765, 1990.

Meyer WH, Houghton JA, Houghton PJ, Webber BL, Look AT. Development and characterization of pediatric osteosarcoma xenografts. Cancer Res 50:2781-2785, 1990.

Houghton JA, Williams LG, de Graaf SSN, Cheshire PJ, Rodman  JR, Maneval  DC, Wainer IW, Jadaud P, Houghton PJ. Relationship between dose rate of [6RS]leucovorin administration, plasma concentrations of reduced folates and pools of 5,10- methylenetetrahydrofolates and tetrahydrofolates in human colon adenocarcinoma xenografts. Cancer Res 50:3493-3502, 1990.

Houghton JA, Williams LG, Cheshire PJ, Wainer IW, Jadaud P, Houghton PJ. Influence of dose of [6RS]leucovorin on reduced folate pools and 5-fluorouracil-mediated thymidylate synthase inhibition in human colon adenocarcinoma  xenografts.  Cancer  Res  50:3940-3946, 1990.

Meyer WH, Loftin SK, Houghton JA, Houghton PJ. Accumulation, intracellular metabolism, and antitumor activity of high- and low-dose methotrexate in human osteosarcoma xenografts.  Cancer Commun 2:219-229, 1990.

Horton JK, Houghton JA, Houghton PJ.  Modulation by verapamil of vincristine retention in an mdr1 overexpressing xenograft and normal mouse tissues: comparison  of  bolus administration and continuous infusion vincristine.  J Cell Pharmacol 1:47-54, 1990.

Bowman LC, Houghton JA, Houghton PJ. Influenced guanine nucleotides on vincristine binding in tumor cytosols and purified tubulin - evidence for an inhibitor of vincristine binding. J Cell Physiol 144:376-382, 1990.

Shapiro DN, Houghton PJ, Hazelton BJ, Germain GS, Murti KG, Houghton JA. Morphologic and molecular characterization of spontaneous myogenic differentiation in a human rhabdomyosarcoma cell line.  Cancer Res 50:6002-6009, 1990.

Thimmaiah KN, Horton JK, Qian X-d, Beck WT, Houghton JA, Houghton PJ. Structural determinants of phenoxazine type compounds required to modulate the accumulation of vinblastine and vincristine in multidrug resistant cell lines.  Cancer Commun 2:249-259, 1990.

Horton JK, Houghton JA, Houghton PJ. Expression of multidrug resistance gene (mdr1) in human tumor xenografts sensitive and resistant to natural products: failure to predict chemosensitivity.  J Cell Pharmacol 2:20-28, 1991.

Houghton JA, Adkins DA, Rahman A, Houghton PJ. Interaction between 5-fluorouracil, [6RS]leucovorin, and recombinant human interferon-a2a in  cultured  colon  adenocarcinoma cells.  Cancer Commun 3:225-231, 1991.

Houghton P, Sosinski J, Thakar J, Houghton  J.  Diarylsulfonylureas:  New anticancer agents with novel activities, toxicities and mechanisms of action. Proc 3rd Inter Congr Neoadj Chemo 405-408, 1991.

Houghton PJ, Rahman A, Wills CL, Dolnick BJ, Houghton JA. Mutation(s) of the thymidylate synthase gene of human adenocarcinoma cells causes a thymidylate synthase- negative phenotype that can be  attenuated  by exogenous  folates.  Cancer  Res  52:558-565, 1992.

Houghton JA, Williams LG, Loftin SK, Cheshire PJ, Morton CL, Houghton PJ, Dayan A, Jolivet J. Factors that influence the therapeutic activity of 5-fluorouracil-[6RS[leucovorin combinations in colon adenocarcinoma xenografts.  Cancer  Chem  Pharmacol  30:423-432, 1992.

Thimmaiah KN, Horton JK, Seshadri R, Israel M, Houghton JA, Harwood FC, Houghton PJ. Synthesis and chemical characterization of N-substituted phenoxazines directed towards reversing vinca alkaloid resistance in multidrug resistant cancer cells. J Med Chem 35:3358- 3364, 1992.

Houghton PJ, Cheshire PJ, Myers H, Stewart CF, Synold TW, Houghton JA.  Evaluation of 9-dimethylaminomethyl-10-hydroxycamptothecin against xenografts derived from adults and childhood solid tumors. Cancer Chemother Pharmacol 31:229-239, 1992.

Gunduz U, Elliott MS, Seubert PH, Houghton JA, Houghton PJ, Trewyn RW, Katze JR. Absence of tRNA-guanine transglycosylase in a human colon adenocarcinoma cell line. Biochim Biophys Acta 1139:229-238, 1992.

Houghton PJ, Cheshire PJ, Hallman JC, Bissery MC, Mathieu-BouÈ A, Houghton JA. Therapeutic efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidinol]-1-piperidino)- carbonyloxy-camptothecin against human tumor xenografts: Lack of cross-resistance in vivo in tumors with acquired resistance to the topoisomerase I inhibitor 9-dimethylaminomethyl-10- hydroxycamptothecin.  Cancer Res 53:2-7, 1993.

Houghton JA, Morton CL, Adkins DA, Rahman A. Locus of the interaction between 5- fluorouracil leucovorin and interferon-a2a in colon carcinoma cells. Cancer Res 53:4243-4250, 1993.

Houghton JA, Williams LG, Adkins DA, Loftin S, Houghton PJ. Comparative efficacy of folate species in expanding reduced folate pools and potentiating 5-fluorouracil cytotoxicity in colon adenocarcinoma cells. Cell Pharmacol 1:53-62, 1994.

Houghton PJ, Cheshire PJ, Hallman JC, Gross JL, McRipley RJ, Sun J-H, Behrens CH, Dexter DL, Houghton JA. Evaluation of a novel bis-naphthalimide, DMP840, against human xenografts derived from adult, juvenile, and pediatric cancers. Cancer Chemother Pharmacol 33:265-272, 1994.

Houghton JA, Harwood FG, Houghton PJ. Cell cycle control processes determine cytostasis or cytotoxicity in thymineless death of colon cancer cells. Cancer Res 54:4967-4973, 1994.

Pratt CB, Meyer WH, Howlett N, Douglass EC, Thompson EI, Bowman LC,  Poe  D, Mounce K, Kun LE, Houghton JA. Phase II study  of  5-fluorouracil/leucovorin  for  pediatric patients with malignant solid tumors. Cancer 74:2593-2598, 1994.

Houghton JA, Cheshire PJ, Morton CL, Stewart CF. Potentiation of 5-fluorouracil- leucovorin activity by interferon-a2a in colon adenocarcinoma xenografts. Clin  Cancer  Res 1:33-40, 1995.

Houghton PJ, Cheshire PJ, Hallman JD, Houghton JA. Therapeutic efficacy of the cyclopropylpyrroloindole, carzelesin (U-80244), against xenografts derived from adult and childhood solid tumors.  Cancer Chemother Pharmacol 36:45-52, 1995.

Houghton PJ, Cheshire PJ, Hallman JD, Lutz L, Friedman HS, Danks MK, Houghton JA. Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol 36:393-403, 1995.

Houghton PJ, Cheshire PJ, Myers L, Lutz L, Toth J, Grindey GB, Houghton JA.  Efficacy of sulofenur and a second generation diarylsulfonylurea, N-[5-(2,3-dihydrobenzofuryl)sulfonyl]- N'-(3,4-dichlorophenyl)urea (LY295501), against colon adenocarcinoma xenografts. Anticancer Drugs 6:317-323, 1995.

Houghton JA, Tillman DM, Harwood FG. The ratio of dATP/dTTP influences the commitment of human colon carcinoma cells to thymineless death. Clin Cancer Res 1:723-730, 1995.

Houghton JA, Cheshire PJ, Hallman JD, Lutz L, Luo X, Li Y, Houghton PJ. Evaluation of irinotecan in combination with 5-fluorouracil or etoposide in xenograft models of colon adenocarcinoma and rhabdomyosarcoma. Clin Cancer Res 2:107-118, 1996.

Thulasi R, Dias P, Houghton PJ, Houghton JA. Interferon-a2a-induced differentiation of human alveolar rhabdomyosarcoma cells: correlation with downregulation of  the  insulin-like growth factor type I receptor. Cell Growth Diff 7:531-541, 1996.

Harwood FG, Frazier MW, Krajewski S, Reed JC, Houghton JA. Acute and delayed apoptosis induced by thymidine deprivation correlates with expression of p53 and p53-regulated genes in colon carcinoma cells. Oncogene 12:2057-2067, 1996.

Houghton PJ, Houghton JA. Antitumor diarylsulfonylureas: Novel agents with unfulfilled promise.  Invest New Drugs 6:1-10, 1996.

Merriman RL, Hertel LW, Schultz RM, Houghton PJ, Houghton  JA, Rutherford  PG, Tanzer LR, Boder GB, Grindey GB. Comparison of the antitumor activity of gemcitabine and ara-C in a panel of human breast, colon, lung and pancreatic xenograft models. Invest New Drugs 14:243-247, 1996.

Houghton PJ, Stewart CF, Zamboni WC, Thompson J, Luo X, Danks MK, Houghton JA. Schedule-dependent efficacy of camptothecins in models of human cancer. Ann NY Acad Sci 803:188-201, 1996.

Houghton JA, Harwood FG, Tillman DM. Thymineless death in colon carcinoma cells is mediated via Fas signaling.  Proc. Natl. Acad. Sci. USA 94:8144-8149, 1997.

Thompson J, Zamboni WC, Cheshire PJ, Lutz L, Luo X, Li Y, Houghton JA, Stewart CF, Houghton PJ. Efficacy of  systemic  administration  of irinotecan  against  neuroblastoma xenografts.  Clin Cancer Res 3:423-431, 1997.

Thompson J, Zamboni WC, Cheshire PJ, Richmond L, Luo X, Houghton JA, Stewart CF, Houghton PJ. Efficacy of oral irinotecan against neuroblastoma xenografts. Anticancer Drugs 8:313-322, 1997.

Hare CB, Elion GB, Houghton PJ, Houghton JA, Keir S, Marcelli SL, Bigner DD, Friedman HS. Therapeutic efficacy of the topoisomerase I inhibitor 7-etheyl-10-(4-[1-piperidinol- 1-piperidino)-carbonyl-oxy-camptothecin against pediatric and adult central nervous  system tumor xenografts. Cancer Chemother Pharmacol 39:187-191, 1997.

Houghton JA, Harwood FG, Gibson AA, Tillman DM. The Fas signaling pathway  is functional in colon carcinoma cells and induces apoptosis. Clin Cancer Res 3:2205-2209, 1997.

Gibson AA,  Harwood FG, Tillman DM,  Houghton JA.  Selective sensitization to DNA damaging agents in a human rhabdomyosarcoma cell line with inducible wild-type p53 overexpression.  Clin Cancer Res 4:145-152, 1998.

Zamboni WC, Stewart CF, Thompson J, Santana V, Cheshire PJ, Richmond LB, Liu X, Poquette C, Houghton JA, Houghton PJ. Relationship between topotecan systemic exposure and tumor response in human neuroblastoma xenografts.  J Natl Cancer Inst 90:505-511, 1998.

Zamboni WC, Stewart CF, Cheshire PJ, Richmond LB, Hanna SK, Luo X, Poquette C, McGovren JP, Houghton JA, Houghton PJ. Studies of the efficacy and pharmacology  of irinotecan against human colon tumor xenograft models.  Clin Cancer Res 4:743-753, 1998.

Tillman DM, Harwood FG, Gibson AA, Houghton JA. Expression of genes that regulate Fas signaling and Fas-mediated apoptosis in colon carcinoma cells. Cell Death Diff. 5:450-457, 1998.

McPake CR, Tillman DM, Poquette CA, George EO, Houghton JA, Harris LC. Bax is an important determinant of chemosensitivity in pediatric tumor cell lines independent of Bcl-2 expression and p53 status.  Oncol Res 10:235-244, 1998.

Houghton JA, Ebanks R, Harwood FG, Tillman DM. Inhibition of apoptosis following thymineless stress is conferred by oncogenic K-ras in colon carcinoma cells. Clin Cancer Res 4:2841-2848, 1998.

Tillman DM, Petak I, Houghton JA. A Fas-dependent component in 5-fluorouracil/ leucovorin-induced cytotoxicity in colon carcinoma cells.  Clin Cancer Res 5:425-430, 1999.

Hwang H-S, Davis TW, Houghton JA, Kinsella TJ. Radiosensitivity of thymidylate synthase-deficient human tumor cells is affected by progression through the G1 restriction point into S-phase: Implications for fluoropyrimidine (FP) radiosensitization (RS). Cancer Res 60:92- 100, 2000.

Harwood FG, Kasibhatla S, Petak I, Vernes R, Green DR, Houghton JA. Regulation of FasL by NF-B and AP-1 in Fas-dependent thymineless death of colon carcinoma cells. J Biol Chem, 275:10023-10029, 2000.

Petak I, Tillman  DM, Harwood  FG, Houghton JA. Fas -dependent and -independent mechanisms of cell death following DNA damage in human colon carcinoma cells. Cancer Res 60:2643-2650,  2000.

Petak I, Douglas L, Tillman DM, Vernes R, Houghton JA. Rhabdomyosarcoma cell lines are resistant to Fas- and highly sensitive to TRAIL-induced apoptosis. Clin Cancer Res 6:4119- 4127, 2000.

Petak I, Tillman DM, Houghton JA.  P53-dependence of Fas induction and acute apoptosis in response to 5-fluorouracil-leucovorin in human  colon carcinoma  cell  lines.  Clin Cancer Res 6:4432-4441, 2000.

Totth A, Sebestyen A, Barna G, Nagy K, Gondor A, Bocsi J, Mihalik R, Petak  I, Houghton J, Kopper L. TGF  beta  1  induces  caspase-dependent  but  death-receptor independent apoptosis in lymphoid cells. Anticancer Res 21:1207-12, 2001.

Schwartzberg L, Petak I, Stewart C, Turner PK, Ashley J, Tillman DM, Douglas L, Mihalik R, Weir A, Tauer K, Shope S, Houghton JA. Modulation of the Fas signaling  pathway  by interferon-in therapy of colon cancer: Phase I trial and correlative studies of interferon-, 5- fluorouracil and leucovorin.  Clin Cancer Res 8:2488-2498, 2002.

Petak I, Danam RP, Tillman DM, Vernes R, Howell SR, Brent TP, Houghton JA. Hypermethylation of the gene promoter and enhancer region can regulate Fas expression and sensitivity in colon carcinoma Cell Death Diff 10:211-217, 2003.

Petak I, Vernes R, Szekely Szuks K, Anozie M, Izeradjene K, Douglas L, Tillman  M, Houghton JA. A caspase-8-independent component in TRAIL/APO2L-induced cell death  in human rhabdomyosarcoma cells. Cell Death Diff 10:729-39, 2003.

Tillman DM, Izeradjene K, Szekely Szucs K, Douglas L and Houghton JA. Rottlerin sensitizes colon carcinoma cells to TRAIL-induced apoptosis via uncoupling of the mitochondria independent of PKC.  Cancer Res 63:5118-5125, 2003.

Gorlick R, Anderson P, Andrulis I, Arndt C, Beardsley GP, Bernstein M, Bridge J, Cheung N-K, Dome JS, Ebb D, Gardner T, Gebhardt M, Grier H, Hansen M, Healey J, Helman L, Hock J, Houghton J, Houghton P, Huvos A, Khanna C, Kieran M, Kleinerman E, Ladanyi M, Lau C, Malkin D,  Marina N, Meltzer P, Meyers P,  Schofield D, Schwartz C, Smith MA,  Toretsky J, Tsokos M, Wexler L, Wigginton J, Withrow S, Schoenfeldt M, Anderson B. Biology of Childhood Osteogenic Sarcoma and Potential Targets for Therapeutic Development. Clin Cancer Res 9: 5442-5453, 2003.

Geller J, Petak I, Szekely Szucs K, Nagy K, Tillman DM, Houghton JA. Interferon--induced sensitization of colon carcinomas to ZD9331 targets caspases,  downstream  of  Fas, independent of mitochondrial signaling and the IAP  survivin.  Clin  Cancer  Res  9:6504-6515 2003.

Turner PK, Houghton JA, Petak I, Tillman DM, Douglas L, Schwartzberg L, Billups C, Tan M,   Panetta   J,   Stewart   CF.   Pharmacokinetics   and  pharmacodynamics   of   subcutaneous interferon gamma in patients receiving 5-fluorouracil and leucovorin. Cancer Chemother Pharmacol 53:253-260, 2004.

Geller JI, Szekely-Szucs K, Petak I, Doyle B, Houghton JA. P21Cip1 is a critical mediator of the cytotoxic action of thymidylate synthase (TS) inhibitors in colorectal  carcinoma  cells. Cancer Res 64:6296-6303, 2004.

Izeradjene K, Douglas L, Delaney A, Houghton  JA. Casein  kinase  I (CKI) attenuates TRAIL-induced apoptosis by regulating the recruitment of FADD and procaspase-8 to the death- inducing signaling complex. Cancer Res 64:8036-8044. 2004.

Izeradjene K, Douglas L, Delaney A, Houghton JA. Influence of Casein Kinase II (CK2) in TRAIL-induced apoptosis in human rhabdomyosarcoma cells. Clin Cancer Res 10:6650-6660, 2004.

Izeradjene K, Douglas L, Delaney A, Martin S, Houghton JA. Casein Kinase II  (CK2) regulates FADD and caspase-8 recruitment to the death-inducing signaling complex (DISC) in TRAIL-induced apoptosis in human colon carcinoma cell lines.  Oncogene 24:2050-2058, 2005.

Izeradjene K, Douglas L, Tillman DM, Delaney AB, Houghton  JA. Reactive oxygen species regulate caspase activation in TRAIL-resistant human colon carcinoma cell  lines. Cancer Res 65:7436-7445, 2005.

Nagy K, Petak I, Imre G, Barna G, Gezane-Csorba M, Sebestyen A, Houghton JA, Mihalik R, Kopper L. Proteasome inhibitors abolish cell death downstream of caspase activation  during anti-microtubule drug-induced apoptosis in leukemia cells. Anticancer Res ;25:3321- 3326, 2005.

Martin S, Phillips DC, Szekely-Szucs K, Elghazi L, Desmots F, Houghton JA. Cyclooxygenase-2 Inhibition sensitizes human colon  carcinoma  cells to  TRAIL-Induced apoptosis through clustering of DR5 and concentrating death-inducing signaling complex components into ceramide-enriched caveolae.   Cancer Res 65:11447-11458, 2005.

Nagy K, Szekely-Szucs K, Izeradjene K, Douglas L, Tillman M, Barti-Juhasz H, Dominici M, Spano C, Luca Cervo G, Conte P, Houghton JA, Mihalik R, Kopper L, Petak I. Proteasome inhibitors sensitize colon carcinoma cells to TRAIL-induced apoptosis via enhanced release of Smac/DIABLO from the mitochondria.  Pathol Oncol Res 12:133-142, 2006.

Phillips DC, Martin S, Doyle BT, Houghton JA. Sphingosine-induced apoptosis in rhabdomyosarcoma cell lines is dependent on pre-mitochondrial Bax activation and post- mitochondrial caspases.  Cancer Res 67:756-764, 2007.

Carew JS, Nawrocki ST, Kahue CN, Zhang H, Yang C, Chung L, Houghton JA, Huang P, Giles FJ, Cleveland JL. Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr- Abl-mediated drug resistance. Blood 110: 313- 322, 2007.

Nawrocki ST, Carew JS, Douglas L, Cleveland JL, Humphreys R, Houghton JA. Histone deacetylase inhibitors enhance lexatumumab-induced apoptosis  via  a  p21Cip1-dependent decrease in survivin levels. Cancer Res 67:6987-6994, 2007.

Phillips DC, Hunt JT, Moneypenny CG, Maclean KH, McKenzie PP, Harris LC, Houghton JA. Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression.  Cell Death Differ 14:1780-1791, 2007.

Carew JS, Nawrocki ST, Reddy VK, Bush D, Rehg JE,  Goodwin  A, Houghton  JA, Casero RA Jr, Marton LJ, Cleveland JL. The novel polyamine analogue CGC-11093 enhances the antimyeloma activity of bortezomib. Cancer Res 68:4783-4790, 2008.

Nawrocki ST, Carew JS, Maclean KH, Courage JF, Huang P, Houghton JA, Cleveland JL, Giles FJ, McConkey DJ. Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of  bortezomib  and  SAHA.  Blood.  112:2917-2926, 2008.

Lobo GP, Waite KA, Planchon SM, Romigh T, Houghton JA, Eng C. ATP modulates PTEN subcellular localization in multiple cancer cell lines. Hum Mol Genet 17:2877-2885, 2008.

Jani TS, Devecchio J, Mazumdar T, Agyeman A, Houghton JA. Inhibition of  NF-kB signaling by quinacrine is cytotoxic to human colon carcinoma cell lines (cc) and is synergistic in combination with TRAIL or oxaliplatin. J.Biol Chem 285:19162-19172, 2010 (PMID 20424169; PMCID: PMC3478462).

Shi T, Mazumdar T, DeVecchio J, Duan Z-H, Agyeman A, Aziz M, Houghton JA. cDNA microarray gene expression profiling of Hedgehog signaling pathway inhibition in human colon cancer cells.  PLoS ONE 5: pii: e13054, 2010 (PMID 20957031; PMCID: PMC2948497).

Mazumdar T, DeVecchio J, Shi T, Jones J, Agyeman A, Houghton JA. Hedgehog (HH) signaling drives cellular survival in human colon carcinoma cells. Cancer Res 71: 1092-1102, 2011 (PMID 21135115; PMCID: PMC3032813).

Dabir S, Kluge A, Aziz MA, Houghton JA, Dowlati A. Identification of STAT3- independent regulatory effects for protein inhibitor of activated STAT3 by binding to novel transcription factors. Cancer Biol Ther 12: 122-134, 2011 (PMID  21532337;  PMCID: PMC3154286).

Mazumdar T, DeVecchio J, Agyeman A, Shi T,  Houghton  JA.  Blocking Hedgehog survival signaling at the level of the GLI genes induces DNA damage and extensive cell death in human colon carcinoma cells. Cancer Res 71:5904-5914, 2011 (PMID 21747117; PMCID: PMC3165104).

Al-Harbi S, Hill B, Mazumder S, Singh K, DeVecchio J, Choudhary G, Rybicki LA, Kalaycio M, Maciejewski JP, Houghton JA, Almasan A.  An anti-apoptotic Bcl-2 family expression index predicts the response of chronic lymphocytic leukemia to ABT-737.  Blood 118:3579-3590, 2011 (PMID 21772052; PMCID: PMC3186334).

Mazumdar T, DeVecchio J, Agyeman A, Shi T, Houghton JA. The GLI genes as the molecular switch in disrupting Hedgehog signaling in colon cancer. Oncotarget 2:638-645, 2011 (PMID 21860067; PMCID: PMC3248207).

Agyeman A, Mazumdar T, Houghton JA.  Regulation  of  DNA  damage following termination of Hedgehog (HH) survival signaling at the level of the GLI genes in human colon cancer.  Oncotarget 8:854-868, 2012 (PMID 22922219; PMCID: PMC3478462).

Mazumdar T, Sandhu R, Qadan M, DeVecchio J, Magloire V, Agyeman A, Li B, Houghton JA. Hedgehog signaling regulates telomerase reverse transcriptase in human cancer cells. PLoS ONE Sep25;8(9): e75253. doi:10.1371/journal.pone.0075253,  2013  (PMID 24086482; PMCID: PMC 3783395).

Agyeman A, Jha B, Mazumdar T, Houghton JA. Mode and specificity of binding of the small molecule GANT61 to GLI determines inhibition of GLI-DNA binding. Oncotarget 5:4492- 4503, 2014 (PMID:24962990; PMCID – in process).

 REVIEW ARTICLES

Houghton JA, Houghton PJ. The xenograft as an intermediary model system: Methods and advantages. In: Hill BT, Dendy P, eds. Human Tumor Drug Sensitivity Testing In Vitro - Techniques and Clinical Applications. New York: Academic Press, pp 179-200, 1983.

Houghton JA, Houghton PJ.5-Halogenated pyrimidines and their nucleosides. In: Fox B, Fox M, eds. Antitumor Drug Resistance-Handbook of Experimental Pharmacology. Berlin: Springer-Verlag, pp 515-549, 1984.

Houghton JA, Houghton PJ. Experimental Chemotherapy in Colon Cancer. In: Levin B, Riddell RH, eds. Comprehensive Oncology - Frontiers in  Gastrointestinal  Cancer.  North Holland: Elsevier, pp 119-138, 1984.

Houghton JA, Houghton PJ. The suitability and use of human tumor xenografts.  In: Kallman R, ed. Rodent tumor models in experimental cancer therapy. Pergamon Press, pp 199- 204, 1987.

Houghton JA, Houghton PJ. Reduced folates and fluoropyrimidine antitumor efficacy. In: Muggia FM, ed. Cancer Chemotherapy: Concepts, Clinical Investigations and Therapeutic Advances.  Kluwer Academic Publishers, pp 23-43, 1989.

Houghton PJ, Houghton JA. Xenografts of pediatric tumors: predictive intermediate models?  In: Modern Trends in Human Leukemia VIII, pp, 149-155, 1989.

Houghton PJ, Horton JK, Houghton JA. Drug sensitivity and resistance in the xenograft model. In: Maurer H, Ruyman R, Pochedly C, eds. In: Rhabdomyosarcomas and related tumors in children.  CRC, 1991.

Houghton PJ, Shapiro DN, Houghton JA. Rhabdomyosarcoma: from the laboratory to the clinic.  Ped Clin of N Amer 38:349-364, 1991.

Houghton JA. Modulation of 5-fluorouracil. In:  Preclinical and Clinical  Modulation of Anticancer Drugs. Academic Press, 1993.

Houghton PJ, Houghton JA. Cellular response to antimetabolite anticancer agents: Cytostasis versus cytotoxicity.  Prog Cell Cycle Research 2:175-185, 1997.

Houghton JA. Apoptosis and drug response. In: Apoptosis and Cancer Chemotherapy. Curr Opin Oncol 11:475-481, 1999.

Houghton JA. Developing novel and highly effective new therapeutic strategies for treatment of colorectal cancer: where do we go from here?  Curr Opin Invest Drugs 2:674-676, 2001.

Petak I, Houghton JA. Shared pathways: death receptors and cytotoxic drugs in cancer therapy.  Pathology Oncology Research 7:95-106, 2001.

Houghton JA. Death receptor signaling in the mechanism of FUra action. In Rustum Y, (ed), In: Fluoropyrimidines in Cancer Therapy, Humana Press Inc., pp 93-105, 2003.

Houghton JA.  Research Philosophy – Profiles and Legacies – Cancer Research: the art of creative thinking.  Cancer Biol and Ther 3:351-355, 2004.

Houghton JA. Antimetabolites. In: Apoptosis and Senescence in Cancer Chemotherapy and Radiotherapy; Holt S, Gewirtz D, Grant S (eds.), Humana Press , pp 361-382, 2007.