Investigational New Drugs

, Volume 21, Issue 1, pp 33–45 | Cite as

Discovery and Preclinical Antitumor Efficacy Evaluations of LY32262 and LY33169

  • Thomas H. Corbett
  • Kathryn White
  • Lisa Polin
  • Juiwanna Kushner
  • Jennifer Paluch
  • Chuan Shih
  • Cora Sue Grossman


The discoveries of a new antitumor agent (LY32262) (N-[2,4-dichlorobenzoyl]phenylsulfonamide) and a close analog (LY33169) are described. For this discovery, a disk-diffusion-soft-agar-colony-formation-assay was used to screen a portion of the Eli Lilly inventory, with the evaluation of each agent against normal cells, leukemic cells and several solid tumors, including a multidrug-resistant solid tumor (with marked selective cytotoxicity for Colon-38 and Human-Colon-15/MDR compared to normal fibroblasts and L1210 leukemic cells characterizing the discovery). In mice, LY32262 and/or LY33169 had curative activity against Colon Adenocarcinoma-38, Human Colon-116, Human Prostate LNCaP, and Human Breast WSU-Br-1. In addition, many other tumors were highly sensitive: Panc-03=2.4 log kill (LK); Panc-02=2.9–4.1 LK; Squamous Lung LC-12=2.1 LK; Colon-26=2.2 LK; AML1498=2.7 LK; Human Sm Cell Lung DMS-273=6.3 LK; Human Squamous Lung 165=3.7 LK; Human Ovarian BG-1=3.7 LK; Human Colon CX-1 (H29)=1.6 LK; Human Colon-15/MDR (a p-glycoprotein positive multidrug resistant tumor)=2.3 LK; Human CNS-gliosarcoma-SF295=3.8 LK. Several tumors were only marginally responsive or totally unresponsive: Mammary Adenocarcinoma-16/C=0.6 LK; Mammary Adenocarcinoma-17=no kill; Colon Adenocarcinoma-11=no kill; L1210 leukemia=1.3 LK; Human Prostate PC-3=0.5 LK; Human Adenosquamous Lung H125=no kill; and Human Breast Adenocarcinoma MX-1=0.9 LK. There was no absolute tissue of origin correlation with antitumor efficacy, although colon tumors were most responsive and mammary tumors least responsive. The cause of the “hit and miss” efficacy has not been determined.

LY32262 LY33169 antitumor preclinical mice 


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  1. 1.
    Corbett TH: A selective two-tumor soft agar assay for drug discovery. Proc Am Assoc Cancer Res 25: 325(#1289), 1984Google Scholar
  2. 2.
    Corbett TH: A selective two-tumor soft agar assay for drug discovery. Proc Am Assoc Cancer Res 26: 332, 1985Google Scholar
  3. 3.
    Corbett TH, Valeriote FA, Polin L, Panchapor C, Pugh S, White K, Lowichik N, Knight J, Bissery M-C, Wozniak A, LoRusso P, Biernat L, Polin D, Knight L, Biggar S, Looney D, Demchik L, Jones J, Jones L, Blair S, Palmer K, Essenmacher S, Lisow L, Mattes KC, Cavanaugh PF, Rake JB, Baker L: Discovery of solid tumor active agents using a soft-agar-colony-formation disk-diffusion-assay. In: Valeriote FA, Corbett TH, Baker LH (eds) Cytotoxic Anticancer Drugs: Models and Concepts for Drug Discovery and Development. Kluwer Academic Publishers, Boston/Dordrecht, London, 1992, pp 33–87Google Scholar
  4. 4.
    Biernat L, Polin L, Corbett T: Adaptation of mammary tumors of mice to a soft agar assay for use in drug discovery. Seventh NCI-EORTC Symposium on New Drugs in Cancer Therapy. Abstract #185, Amsterdam, March 17–20, 1992Google Scholar
  5. 5.
    Corbett T, Valeriote F, LoRusso P, Polin L, Panchapor C, Pugh S, White K, Knight J, Demchik L, Jones J, Jones L, Lowichik N, Biernat L, Foster B, Wozniak A, Lisow L, Valdivieso M, Baker L, Leopold W, Sebolt J, Bissery M-C, Mattes K, Dzubow J, Rake J, Perni R, Wentland M, Coughlin S, Shaw JM, Liverside G, Liversidge E, Bruno J, Sarpotdar P, Moore R, Patterson G: Tumor models and the discovery and secondary evaluation of solid tumor active agents. Int J Pharmacog 33(Suppl): 102–122, 1995Google Scholar
  6. 6.
    Corbett TH, Panchapor C, Polin L, Lowichik N, Pugh S, White K, Kushner J, Meyer J, Czarnecki J, Chinnukroh S, Edelstein M, LoRusso P, Heilbrun L, Horwitz JP, Grieshaber C, Perni R, Wentland M, Coughlin S, Elenbaas S, Philion R, Rake J: Preclinical efficacy of thioxanthone SR-271425 against transplanted solid tumors of mouse and human origin. Invest New Drugs 17: 17–27, 1999Google Scholar
  7. 7.
    Corbett TH, Valeriote FA, Demchik L, Lowichik N, Polin L, Panchapor C, Pugh S, White K, Kushner J, Rake J, Wentland M, Golakoti T, Hetzel C, Ogino J, Patterson G, Moore R: Discovery of cryptophycin-1 and BCN-183577: examples of strategies and problems in the detection of antitumor activity in mice. Invest New Drugs 15: 207–218, 1997Google Scholar
  8. 8.
    Corbett TH, Valeriote FA, Demchik L, Polin L, Panchapor C, Pugh S, White K, Kushner J, Jones J, Jones L, Foster B, Wiegand R, Lisow L, Golakoti T, Heltzel C, Ogino J, Patterson G, Moore R: Preclinical anticancer activity of Cryptophycin-8. J Exp Therapeut Oncol 1: 95–108, 1996Google Scholar
  9. 9.
    Corbett T, Lowichik N, Pugh S, Polin L, Panchapor C, White K, Knight J, Demchik L, Jones J, Jones L, Biernat L, LoRusso P, Foster B, Heibrun L, Rake J, Mattes KC, Perni R, Powles RG, Hiavac AG, Wentland MP, Coughlin SA, Baker L, Valeriote F: Antitumor activity of N-[[1–[[2–(Diethylamino)ethyl]amino]-9–oxo-9H-Thioxanthen-4–Y1]methyl] methanesulfonamide (WIN33377) and analogs. Expert Opin Invest Drugs 3(12): 1281–1292, 1994Google Scholar
  10. 10.
    Corbett TH, LoRusso P, Demchick L, Simpson C, Pugh S, White K, Kushner J, Polin L, Meyer J, Czarnecki J, Heilbrun L, Horwitz JP, Gross JL, Behrens CH, Harrison BA, McRipley RJ, Trainor G: Preclinical antitumor efficacy of analogs of XK-469: sodium-(2–[4–(7–chloro-2–quinoxalinyloxy)phenoxy]propionate. Invest New Drugs 16: 129–139, 1998Google Scholar
  11. 11.
    Schabel FM Jr, Trader MW, Laster WR Jr, Corbett TH, Griswold DP Jr: Cis-dichlorodiammineplatinum (II): combination chemotherapy and cross-resistance studies with tumors of mice. Cancer Treat Rep 63: 1459–1473, 1979Google Scholar
  12. 12.
    Schabel FM Jr, Skipper HE, Trader MW, Laster WR Jr, Griswold DP Jr, Corbett TH: Establishment of cross-resistance profiles for new agents. Cancer Treat Rep 67: 905–922, 1983Google Scholar
  13. 13.
    Corbett TH, Valeriote FA: Rodent Models in Experimental Chemotherapy. In: Kallman RF (ed.) Rodent Tumor Models in Experimental Cancer Therapy. Pergamon Press, New York, 1987, Chapter 50, pp 233–247Google Scholar
  14. 14.
    Corbett TH, Bissery MC, LoRusso PM, Polin L: 5–Fluorouracil containing combinations in murine tumor systems. Invest New Drugs 7: 37–49, 1989Google Scholar
  15. 15.
    Corbett T, Valeriote F, Baker L: Is the P388 murine tumor no longer adequate as a drug discovery model? Invest New Drugs 5: 3–20, 1987Google Scholar
  16. 16.
    Corbett T, Valeriote F, LoRusso P, Polin L, Panchapor C, Pugh S, White K, Knight J, Demchik L, Jones J, Jones L, Lisow L: In vivo methods for screening and preclinical testing; use of rodent solid tumors for drug discovery. In: Teicher B (ed.) Anticancer Drugs Development Guide: Preclinical Screening, Clinical Trials, and Approval. Humana Press Inc., Totowa, New Jersey, 1997, Chapter 5, pp 75–99Google Scholar
  17. 17.
    Polin L, Valeriote F, White K, Panchapor C, Pugh S, Knight J, LoRusso P, Hussain M, Liversidge E, Shaw M, Golakoti T, Patterson G, Moore R, Corbett TH: Treatment of human prostate tumors PC-3 and TSU-PR1 with standard and investigational agents in SCID mice. Invest New Drugs 15: 99–108, 1997Google Scholar
  18. 18.
    Corbett TH, Polin L, Roberts BJ, Lawson AJ, Leopold III WR, White K, Kushner J, Paluch J, Hazeldine S, Moore R, Rake J, Horwitz JP: Transplantable syngeneic rodent tumors: solid tumors of mice. In: B. Teicher (ed.) Tumor Models in Cancer Research. Humana Press Inc., Totowa, NJ, 2001 Chapter 3, pp 41–71Google Scholar
  19. 19.
    Corbett TH, Leopold WR, Dykes DJ, Roberts BJ, Griswold DP Jr, Schabel FM Jr: Toxicity and anticancer activity of a new triazine antifolate (NSC-127755). Cancer Res 42: 1707–1715, 1982Google Scholar
  20. 20.
    LoRusso PM, Wozniak AJ, Polin L, Capps D, Leopold WR, Werbel LM, Biernat L, Dan ME, Corbett TH: Antitumor efficacy of PD115934 (NSC 366140) against solid tumors of mice. Cancer Res 50: 4900–4905, 1990Google Scholar
  21. 21.
    Corbett TH, Griswold DP Jr, Roberts BJ, Peckham JC, Schabel FM Jr: Tumor induction relationships in development of transplantable cancers of the colon in mice for chemotherapy assays, with a note on carcinogen structure. Cancer Res 35: 2434–2439, 1975Google Scholar
  22. 22.
    Corbett TH, Griswold Jr DP, Roberts BJ, Peckham JC, Schabel Jr FM: Evaluation of single agents and combinations of chemotherapeutic agents in mouse colon carcinomas. Cancer 40(5): 2660–2680, 1977Google Scholar
  23. 23.
    Corbett TH, Griswold Jr DP, Roberts BJ, Peckham JC, Schabel Jr FM: Biology and therapeutic response of a mouse mammary adenocarcinoma (16/C) and its potential as a model for surgical adjuvant chemotherapy. Cancer Treat Rep 62(10): 1471–1488, 1978Google Scholar
  24. 24.
    Schabel FM Jr, Skipper HE, Trader MW, Laster WR Jr, Griswold DP Jr, Corbett TH: Establishment of cross-resistance profiles for new agents. Cancer Treat Rep 67: 905–922, 1983. Corrected tables published in Cancer Treat Rep 68: 453–459, 1984Google Scholar
  25. 25.
    Kessel D, Corbett TH: Correlations between anthracycline resistance, drug accumulation and membrane glycoprotein patterns in solid tumors of mice. Cancer Lett 28: 187–193, 1985Google Scholar
  26. 26.
    Corbett TH, Roberts BJ, Leopold WR, Peckham JC, Wilkoff LJ, Griswold DP Jr, Schabel FM Jr: Induction and chemotherapeutic response of two transplantable ductal adenocarcinomas of the pancreas in C57BL/6 mice. Cancer Res 44: 717–726, 1984Google Scholar
  27. 27.
    Smith WE, Yazdi E, Miller L: Carcinogenesis in pulmonary epithelia in mice on different levels of Vitamin A. Environ Res 5: 152–163, 1972Google Scholar
  28. 28.
    Tapazoglou E, Polin L, Corbett TH, Al-Sarraf M: Chemotherapy of the squamous cell lung cancer LC-12 with 5–fluorouracil, cisplatin, carboplatin or iproplatin combinations. Invest New Drugs 6(4): 259–264, 1988Google Scholar
  29. 29.
    Law LW, Dunn TB, Boyle PJ, Miller JH: Observations on the effect of folic-acid antagonists on transplantable lymphoid leukemias in mice. J Natl Cancer Inst 10: 179–192, 1949Google Scholar
  30. 30.
    Bradner WT, Pindell MH: Myeoid Leukemia C1498 as a screen for cancer chemotherapeutic agents. Cancer Res 26(April, part 2): 375–390, 1966Google Scholar
  31. 31.
    Dawe CJ, Potter M: Morphologic and biologic progression of a lymphoid neoplasm of the mouse in vivo and in vitro. Am J Pathol 33: 603, 1957 (Abstract).Google Scholar
  32. 32.
    Kaighn ME, Lechner JF, Babcock MS, Marnell M, Ohnuki Y, Narayan KS: The pasadena cell lines. Prog Clin Biol Res 37: 85–109, 1980Google Scholar
  33. 33.
    Horoszewicz JS, Leong SS, Chu TM, Wajsman ZL, Friedman M, Papsidero L, Kim J, Chai LS, Kakati S, Arya SK, Sandberg AA: The LNCaP cell line — A new model for studies on human prostatic carcinoma. In: Murphy GP (ed.) Models for Prostatic Cancer. Alan R Liss Inc., New York, 1980, pp 115–132Google Scholar
  34. 34.
    Brower H, Carney DN, Oie HK, Gazdar AF, Minna JD: Growth of cell lines and clinical specimens of human non-small cell lung cancer in a serum-free defined medium. Cancer Res 46: 798–806, 1986Google Scholar
  35. 35.
    Brattain MG, Fine WD, Khaled FM, Thomson J, Brattain DE: Heterogeneity of malignant cells from a human colonic carcinoma. Cancer Res 41: 1751–1756, 1981Google Scholar
  36. 36.
    Dexter DL, Barbosa JA, Calabresi P: N,N-dimethylformamide-induce alteration of cell culture characteristics and loss of tumorigenicity in cultured human colon carcinoma cells. Cancer Res 39: 1020–1025, 1979Google Scholar
  37. 37.
    Alvarez M, Paull K, Monks A, Hose C, Lee J-S, Weinstein J, Grever M, Bates S, Fojo T: Generation of a drug resistance profile by quantitation of mdr-1/P-glycoprotein in the cell lines of the National Cancer Institute Anticancer Drug Screen. J Clin Invest 95: 2205–2214, 1995Google Scholar
  38. 38.
    LoRusso PM, Polin L, Visscher D, Jones J, Jones LA, Demchik L, Kushner J, Corbett TH: WSU-Br1: A novel human breast xenograft model. Proc Am Assoc Cancer Res 36: 311, 1995Google Scholar
  39. 39.
    Plowman J, Dykes DJ, Hollingshead M, Simpson-Herren L, Alley MC: Human tumor xenograft models in NCI drug development. In: Teicher B (ed.) Anticancer Drugs Development Guide: Preclinical Screening, Clinical Trials, and Approval. Humana Press Inc., Totowa, New Jersey, 1997, Chapter 6, pp 75–99Google Scholar
  40. 40.
    Giovannella BC, Stehlin JS, Shepard RC: 1977, Proc Intl Workshop Nude Mice, 2nd Tokyo, 1976, pp 475–481Google Scholar
  41. 41.
    Geisinger KR, Kute TE, Pettenati MJ, Welander CE, Dennard Y, Collins LA, Berens ME: Characterization of a human ovarian carcinoma cell line with estrogen and progesterone receptors. Cancer 15: 280–288, 1989Google Scholar
  42. 42.
    Bogden AE, Taylor JE, Moreau J-P, Coy DH, LePage DJ: Response of human lung xenografts to treatment with a somatostatin analogue (Somatuline). Cancer Res 50: 4360–4365, 1990Google Scholar
  43. 43.
    Fogh J, Trempe G: New human tumor cell lines. Chapter 5. In: Fogh J. (ed) Human Tumor Cells In Vitro. Plenum Publ Corp, New York, 1975, pp 115–159Google Scholar
  44. 44.
    Rutka JT, Giblin JR, Hoifodt HK, Dougherty DV, Bell CW, McCulloch JR, Davis RL, Wilson CB, Rosenblum ML: Establishment and characterization of a cell line from a human gliosarcoma. Cancer Res 46: 5893–5902, 1986Google Scholar
  45. 45.
    Pettengill OS, Sorenson GD, Wurster-Hill DH, Curphey TJ, Noll WW, Cate CC, Muaurer LH: Isolation and growth characteristics of continuous cell lines from small-cell carcinoma of the lung. Cancer 45: 906–918, 1980Google Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Thomas H. Corbett
    • 1
  • Kathryn White
    • 1
  • Lisa Polin
    • 1
  • Juiwanna Kushner
    • 1
  • Jennifer Paluch
    • 1
  • Chuan Shih
    • 2
  • Cora Sue Grossman
    • 2
  1. 1.Barbara Ann Karmanos Cancer InstituteWayne State University School of MedicineDetroitUSA
  2. 2.Lilly Corporate CenterEli Lilly CorporationIndianapolisUSA

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