There are no bad anticancer agents, only bad clinical trial designs--twenty-first Richard and Hinda Rosenthal Foundation Award Lecture.

Unfortunately, the vast majority (90%) of new anticancer agents designed in the laboratory never make it into routine clinical use. The hypothesis of this lecture is that many new agents fail in the clinic because the appropriate clinical trial(s) that could exploit the attributes of the new agent are not performed. An appreciation that both bench and clinical investigations are difficult endeavors should aid in improving clinical trial designs and give the best chance for new agents to be added to our therapeutic armamentarium.

[1]  A. Sjoerdsma,et al.  Phase I trial and pharmacokinetic studies of alpha-difluoromethylornithine--an inhibitor of polyamine biosynthesis. , 1984, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  S. Broder,et al.  Acquired immunodeficiency syndrome and non-Hodgkin's lymphomas. , 1991, Cancer research.

[3]  H. Scher,et al.  Methylglyoxal-bis(guanylhydrazone) in hormone-resistant adenocarcinoma of the prostate. , 1985, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  R. H. Levin,et al.  Treatment of acute leukemia with methylglyoxal‐bis‐guanylhydrazone (methyl GAG) , 1965, Clinical pharmacology and therapeutics.

[5]  D. Russell Increased polyamine concentrations in the urine of human cancer patients. , 1971, Nature: New biology.

[6]  J. V. Von Roenn,et al.  Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin's lymphoma associated with human immunodeficiency virus infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. , 1997, The New England journal of medicine.

[7]  K. Marsh,et al.  Plasma levels and urinary excretion of methyl-GAG following iv infusion in man. , 1981, Cancer treatment reports.

[8]  J. Thiele,et al.  Zur Kenntniss des Amidoguanidins. I. Condensationsproducte des Amidoguanidins mit Aldehyden und Ketonen der Fettreihe , 1898 .

[9]  J. DiPaolo,et al.  The antimitochondrial action of 2-choloro-4', 4"-bis(2-imidazolin-2-yl)terephthalanilide and methylglyoxal bis(guanylhydrazone). , 1966, Cancer research.

[10]  L. Andersson,et al.  Ornithine decarboxylase activity is critical for cell transformation , 1992, Nature.

[11]  J. Holland,et al.  The memorial pain assessment card. A valid instrument for the evaluation of cancer pain , 1987, Cancer.

[12]  L. Meeker,et al.  Effect of concentration of D,L-2-difluoromethylornithine on murine mammary carcinogenesis. , 1985, Cancer research.

[13]  A. Abioye,et al.  Pancreatic carcinoma. , 2020, Journal of the National Medical Association.

[14]  W. Regelson,et al.  Clinical experience with methylglyoxal bis (guanylhydrazone) dihydrochloride: a new agent with clinical activity in acute myelocytic leukemia and the lymphomas. , 1963, Cancer chemotherapy reports.

[15]  V. Steele,et al.  Surrogate endpoint biomarkers for phase II cancer chemoprevention trials. , 1994, Journal of cellular biochemistry. Supplement.

[16]  L. Hertel,et al.  Evaluation of the antitumor activity of gemcitabine (2',2'-difluoro-2'-deoxycytidine). , 1990, Cancer research.

[17]  P. Gimotty,et al.  Prognostic influence on survival of increased ornithine decarboxylase activity in human breast cancer. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[18]  D. V. Von Hoff,et al.  Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  L. Hertel,et al.  Action of 2',2'-difluorodeoxycytidine on DNA synthesis. , 1991, Cancer research.

[20]  A. Levine,et al.  Acquired immunodeficiency syndrome-related lymphoma , 2003 .

[21]  R. Birch,et al.  Mitoguazone in advanced squamous cell carcinoma of head and neck origin: a phase II trial of the Southeastern Cancer Study Group. , 1986, Cancer treatment reports.

[22]  D. Alberts,et al.  Dose de-escalation chemoprevention trial of alpha-difluoromethylornithine in patients with colon polyps. , 1994, Journal of the National Cancer Institute.

[23]  V. Heinemann,et al.  Comparison of the cellular pharmacokinetics and toxicity of 2',2'-difluorodeoxycytidine and 1-beta-D-arabinofuranosylcytosine. , 1988, Cancer research.

[24]  C. Levy,et al.  Urinary polyamines in cancer patients. , 1971, Cancer research.

[25]  J. Burchenal,et al.  Methylglyoxal-bis(guanylhydrazone) (Methyl-GAG): current status and future prospects. , 1983, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  D. Kramer,et al.  Independence of drug action on mitochondria and polyamines in L1210 leukemia cells treated with methylglyoxal-bis(guanylhydrazone). , 1980, Cancer research.

[27]  D. V. Von Hoff,et al.  Phase I clinical trial of gemcitabine given as an intravenous bolus on 5 consecutive days. , 1994, European journal of cancer.

[28]  H. Thaler,et al.  Pain and depression in patients with newly diagnosed pancreas cancer. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  Jayashree,et al.  Chemoprevention of colon carcinogenesis by concurrent administration of piroxicam, a nonsteroidal antiinflammatory drug with D,L-alpha-difluoromethylornithine, an ornithine decarboxylase inhibitor, in diet. , 1990, Cancer research.

[30]  R. Warrell,et al.  Effectiveness of methyl-GAG (methylglyoxal-bis[guanylhydrazone]) in patients with advanced malignant lymphoma. , 1981, Blood.

[31]  A. Harris,et al.  Phase II study of gemcitabine in patients with advanced pancreatic cancer. , 1996, British Journal of Cancer.

[32]  S. Hilsenbeck,et al.  Activity of 2, 2 -difluorodeoxycytidine (Gemcitabine) against human tumor colony forming units , 1992, Anti-cancer drugs.

[33]  A. Pegg,et al.  Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy. , 1988, Cancer research.

[34]  P. Sperryn,et al.  Blood. , 1989, British journal of sports medicine.

[35]  G. Wilding,et al.  Randomized phase I chemoprevention dose-seeking study of alpha-difluoromethylornithine. , 1993, Journal of the National Cancer Institute.

[36]  C. Porter,et al.  Polyamine biosynthetic activity in normal and neoplastic human colorectal tissues , 1987, Cancer.

[37]  A. Schenone,et al.  Specific inhibition of the enzymic decarboxylation of S-adenosylmethionine by methylglyoxal bis(guanylhydrazone) and related substances. , 1974, The Biochemical journal.

[38]  Y. Homma,et al.  Inhibition of N-butyl-N-(4-hydroxybutyl)nitrosamine-induced rat urinary bladder carcinogenesis by alpha-difluoromethylornithine. , 1987, Cancer research.

[39]  T. Slaga,et al.  alpha-Difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, inhibits tumor promoter-induced polyamine accumulation and carcinogenesis in mouse skin. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[40]  R. Sampliner,et al.  Ornithine decarboxylase activity in Barrett's esophagus: a potential marker for dysplasia. , 1988, Gastroenterology.

[41]  R. Benjamin,et al.  Penetration of methylglyoxal bis(guanylhydrazone) into intracerebral tumors in humans. , 1981, Cancer research.

[42]  R. Lotan,et al.  Phase I dose de-escalation trial of alpha-difluoromethylornithine in patients with grade 3 cervical intraepithelial neoplasia. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[43]  D. V. Von Hoff,et al.  MGBG: teaching an old drug new tricks. , 1994, Annals of oncology : official journal of the European Society for Medical Oncology.

[44]  W. Plunkett,et al.  Modulatory activity of 2',2'-difluorodeoxycytidine on the phosphorylation and cytotoxicity of arabinosyl nucleosides. , 1990, Cancer research.

[45]  D. Byar,et al.  Clinical predictivity of transplantable tumor systems in the selection of new drugs for solid tumors: rationale for a three-stage strategy. , 1983, Cancer treatment reports.

[46]  A. Levine Acquired immunodeficiency syndrome-related lymphoma [see comments] , 1992 .

[47]  D. V. Von Hoff,et al.  A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. , 1996, Annals of oncology : official journal of the European Society for Medical Oncology.

[48]  H Schipper,et al.  Shifting the cancer paradigm: must we kill to cure? , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  E. Freireich,et al.  Methylglyoxal bis (guanylhydrazone): a new agent active against acute myelocytic leukemia. , 1962, Cancer chemotherapy reports.

[50]  A. Tulpule,et al.  Mitoguazone therapy in patients with refractory or relapsed AIDS-related lymphoma: results from a multicenter phase II trial. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.