Critical analysis of carcinogenicity study outcomes. Relationship with pharmacological properties

Abstract Predicting the outcome of life-time carcinogenicity studies in rats based on chronic (6-month) toxicity studies in this species is possible in some instances. This should reduce the number of such studies and hence have a significant impact on the total number of animals used in safety assessment of new medicines. From a regulatory perspective, this should be sufficient to grant a waiver for a carcinogenicity study in those cases where there is confidence in the outcome of the prediction. Pharmacological properties are a frequent key factor for the carcinogenic mode of action of some pharmaceuticals, but data-analysis on a large dataset has never been formally conducted. We have conducted an analysis of a dataset based on the perspective of the pharmacology of 255 compounds from industrial and regulatory sources. It is proposed that a pharmacological, class-specific, model may consist of an overall causal relationship between the pharmacological class and the histopathology findings in rats after 6 months treatment, leading to carcinogenicity outcome after 2 years. Knowledge of the intended drug target and pathway pharmacology should enhance the prediction of either positive or negative outcomes of rat carcinogenicity studies. The goal of this analysis is to review the pharmacological properties of compounds together with the histopathology findings from the chronic toxicity study in rodents in order to introduce an integrated approach to estimate the risk of human carcinogenicity of pharmaceuticals. This approach would allow scientists to define conditions under which 2-year rat carcinogenicity studies will or will not add value to such an assessment. We have demonstrated the possibility of a regulatory waiver for a carcinogenicity study in rats, as currently discussed in the International Council for Harmonization (ICH) – formerly known as the International Conference on Harmonization (ICH), by applying the proposed prediction approach in a number of case studies.

[1]  W. Edwards,et al.  Cell proliferation in carcinoid valve disease: a mechanism for serotonin effects. , 2001, The Journal of heart valve disease.

[2]  M. Sales,et al.  Muscarinic receptors are involved in LMM3 tumor cells proliferation and angiogenesis. , 2005, Biochemical and biophysical research communications.

[3]  A. Gough,et al.  Pancreatic acinar cell neoplasia in male Wistar rats following 2 years of gabapentin exposure. , 1995, Toxicology.

[4]  R. Michael McClain,et al.  The Significance of Hepatic Microsomal Enzyme Induction and Altered Thyroid Function in Rats: Implications for Thyroid Gland Neoplasia , 1989, Toxicologic pathology.

[5]  L. B. Knudsen.  Liraglutide: the therapeutic promise from animal models , 2010, International journal of clinical practice. Supplement.

[6]  B. Water,et al.  Classifying the adverse mitogenic mode of action of insulin analogues using a novel mechanism-based genetically engineered human breast cancer cell panel , 2014, Archives of Toxicology.

[7]  P. Newberne,et al.  Lack of carcinogenicity of oxprenolol, a β-adrenergic blocking agent , 1977 .

[8]  A. McTiernan,et al.  Use of antihypertensive medications and breast cancer risk , 2012, Cancer Causes & Control.

[9]  A. Zuckerman,et al.  IARC Monographs on the Evaluation of Carcinogenic Risks to Humans , 1995, IARC monographs on the evaluation of carcinogenic risks to humans.

[10]  S. Safe,et al.  Sulindac sulfide inhibits colon cancer cell growth and downregulates specificity protein transcription factors , 2015, BMC Cancer.

[11]  B. Harrison.  Endocrine Surgical Aspects of Multiple Endocrine Neoplasia Syndromes in Children , 2007, Hormone Research in Paediatrics.

[12]  S. Filetti,et al.  PDE5 expression in human thyroid tumors and effects of PDE5 inhibitors on growth and migration of cancer cells , 2015, Endocrine.

[13]  F. Tingley,et al.  Pharmacological Effects of Nicotine on Norepinephrine Metabolism in Rat Brown Adipose Tissue: Relevance to Nicotinic Therapies for Smoking Cessation , 2008, Toxicologic pathology.

[14]  S. Carobbio,et al.  Dopamine D2-like Receptors Are Expressed in Pancreatic Beta Cells and Mediate Inhibition of Insulin Secretion* , 2005, Journal of Biological Chemistry.

[15]  K. Turteltaub,et al.  Tamoxifen DNA damage detected in human endometrium using accelerator mass spectrometry. , 2003, Cancer research.

[16]  R. Cox,et al.  Carcinogenicity and mutagenicity studies with fluvastatin, a new, entirely synthetic HMG-CoA reductase inhibitor. , 1994, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[17]  G. Williams,et al.  Major difference in the hepatocarcinogenicity and DNA adduct forming ability between toremifene and tamoxifen in female Crl:CD(BR) rats. , 1993, Cancer research.

[18]  J. Vaidya,et al.  Role of glucocorticoids in breast cancer. , 2010, Current pharmaceutical design.

[19]  A. Sjölander,et al.  CysLT1R Antagonists Inhibit Tumor Growth in a Xenograft Model of Colon Cancer , 2013, PloS one.

[20]  J. MacDonald,et al.  Studies on the effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on the rodent forestomach. , 1991, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[21]  R. J. Gerson,et al.  Weight-of-Biological Evidence Approach for Assessing Carcinogenicity , 1988 .

[22]  A. Funakoshi,et al.  Acetylcholine regulates pancreastatin secretion from the human pancreastatin-producing cell line (QGP-1N). , 1991, The Journal of clinical endocrinology and metabolism.

[23]  R. Jensen,et al.  Human colon cancer cell proliferation mediated by the M3 muscarinic cholinergic receptor. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[24]  L. Iversen,et al.  Generalized Cellular Hypertrophy is Induced by a Dual-Acting PPAR Agonist in Rat Urinary Bladder Urothelium In Vivo , 2005, Toxicologic pathology.

[25]  M. Cano,et al.  Urothelial carcinogenesis in the urinary bladder of male rats treated with muraglitazar, a PPAR alpha/gamma agonist: Evidence for urolithiasis as the inciting event in the mode of action. , 2006, Toxicologic pathology.

[26]  C. Drachenberg,et al.  Acetylcholine release by human colon cancer cells mediates autocrine stimulation of cell proliferation. , 2008, American journal of physiology. Gastrointestinal and liver physiology.

[27]  S. Suissa,et al.  The use of atypical antipsychotics and the risk of breast cancer , 2011, Breast Cancer Research and Treatment.

[28]  T. Slaga,et al.  Differential effects on lung cancer cell proliferation by agonists of glucocorticoid and PPARα receptors , 2014, Molecular carcinogenesis.

[29]  R. J. Martin,et al.  Atlas of experimental toxicological pathology , 1989, Veterinary Research Communications.

[30]  B. Cooke,et al.  Effect of a dopamine agonist on the development of Leydig cell hyperplasia in Sprague-Dawley rats. , 1996, Toxicology and applied pharmacology.

[31]  G. Carruba,et al.  Androgen metabolism and biotransformation in nontumoral and malignant human liver tissues and cells , 2009, The Journal of Steroid Biochemistry and Molecular Biology.

[32]  R. Reynolds,et al.  Calcium channel blockers and cancer: a risk analysis using the UK Clinical Practice Research Datalink (CPRD) , 2016, BMJ Open.

[33]  A. Jacobs.  Prediction of 2-year carcinogenicity study results for pharmaceutical products: how are we doing? , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[34]  S. Hügl,et al.  Prolactin stimulates proliferation of the glucose-dependent beta-cell line INS-1 via different IRS-proteins. , 2007, JOP : Journal of the pancreas.

[35]  B. Lima,et al.  Mechanisms of nongenotoxic carcinogenesis and assessment of the human hazard. , 2000 .

[36]  Daniel Morton,et al.  An Analysis of Pharmaceutical Experience with Decades of Rat Carcinogenicity Testing , 2011, Toxicologic pathology.

[37]  Sense and non-sense in toxicity assessment of medicinal products , 1997 .

[38]  Samuel M Cohen,et al.  Human carcinogenic risk evaluation: an alternative approach to the two-year rodent bioassay. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[39]  C. Fenoglio-Preiser,et al.  Acetylcholinesterase supports anchorage independence in colon cancer , 2008, Clinical & Experimental Metastasis.

[40]  G. Rodan,et al.  The effects of the aminobisphosphonate alendronate on thyroid hormone-induced osteopenia in rats , 1993, Calcified Tissue International.

[41]  S. Soodvilai,et al.  Pulmonary , gastrointestinal and urogenital pharmacology Pranlukast inhibits renal epithelial cyst progression via activation of AMP-activated protein kinase , 2014 .

[42]  L. Iversen,et al.  Biomarkers for early effects of carcinogenic dual-acting PPAR agonists in rat urinary bladder urothelium in vivo , 2005, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[43]  D. J. Lewis,et al.  The Endocrine Glands , 1987 .

[44]  J. Contrera,et al.  Carcinogenicity testing and the evaluation of regulatory requirements for pharmaceuticals. , 1997, Regulatory toxicology and pharmacology : RTP.

[45]  S. Hankinson,et al.  A prospective study of plasma prolactin concentrations and risk of premenopausal and postmenopausal breast cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[46]  J W Green,et al.  A review of the genotoxicity of marketed pharmaceuticals. , 2001, Mutation research.

[47]  K. Ramana,et al.  Aldose reductase deficiency in mice prevents azoxymethane-induced colonic preneoplastic aberrant crypt foci formation. , 2009, Carcinogenesis.

[48]  H. Sasano,et al.  Aromatase in human liver and its diseases , 2013, Cancer medicine.

[49]  F. Bellanti,et al.  Carcinogenicity of Biopharmaceuticals , 2015 .

[50]  D. Wallace,et al.  Tolvaptan inhibits ERK-dependent cell proliferation, Cl⁻ secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin. , 2011, American journal of physiology. Renal physiology.

[51]  A. Martelli,et al.  Genotoxicity and carcinogenicity studies of antihistamines , 2011, Archives of Toxicology.

[52]  C. Capen,et al.  Neoplastic Lesions of Questionable Significance to Humans , 1994, Toxicologic pathology.

[53]  V. Petrozza,et al.  M2 muscarinic receptors inhibit cell proliferation and migration in urothelial bladder cancer cells , 2017 .

[54]  M. Valenzuela,et al.  A rat mammary tumor model induced by the organophosphorous pesticides parathion and malathion, possibly through acetylcholinesterase inhibition. , 2001, Environmental health perspectives.

[55]  K. Teerds,et al.  Effect of a Dopamine agoniste on the development of Leydig cellhyperplasia in Sprague-Dawley rats , 1996 .

[56]  Steven A. Bailey,et al.  Carcinogenicity and hormone studies with the tissue‐selective estrogen receptor modulator bazadoxifene , 2013, Journal of cellular physiology.

[57]  Michael J. Keiser,et al.  Predicting new molecular targets for known drugs , 2009, Nature.

[58]  Ronac Mamtani,et al.  Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes. , 2015, JAMA.

[59]  C. Furberg,et al.  Is the Use of Some Calcium Antagonists Linked to Cancer? , 1998, Drugs & aging.

[60]  D. Poynter,et al.  Beta-adrenoceptor stimulants and mesovarian leiomyomas in the rat. , 1983, Toxicology.

[61]  A. Lampo,et al.  Differential responses to JNJ‐37822681, a specific and fast dissociating dopamine D2 receptor antagonist, in cynomolgus monkey and Sprague–Dawley rat general toxicology studies: clinical observations, prolactin levels, mammary histopathology findings and toxicokinetics , 2014, Journal of applied toxicology : JAT.

[62]  F. Roe,et al.  Enzootic and Epizootic Adrenal Medullary Proliferative Disease of Rats: Influence of Dietary Factors which Affect Calcium Absorption , 1985, Human toxicology.

[63]  A. Tischler,et al.  Vitamin D3-induced proliferative lesions in the rat adrenal medulla. , 1999, Toxicological sciences : an official journal of the Society of Toxicology.

[64]  A. Nishikawa,et al.  Influences of long-term administration of 24R, 25-dihydroxyvitamin D3, a vitamin D3 derivative, in rats. , 1999, The Journal of toxicological sciences.

[65]  T. Jessell,et al.  Ectopic expression of the serotonin 1c receptor and the triggering of malignant transformation. , 1989, Science.

[66]  Russell Huby,et al.  Inhibition of Oestradiol‐induced Prolactin Release in a Dual‐Cannulated Ovariectomized Rat Model by Carmoxirole, a Peripherally Restricted Dopamine Agonist , 2012, Basic & clinical pharmacology & toxicology.

[67]  M. Rogawski,et al.  New molecular targets for antiepileptic drugs: alpha(2)delta, SV2A, and K(v)7/KCNQ/M potassium channels. , 2008, Current Neurology and Neuroscience Reports.

[68]  Y. Nakata,et al.  Serotonin (5‐HT) induces glial cell line‐derived neurotrophic factor (GDNF) mRNA expression via the transactivation of fibroblast growth factor receptor 2 (FGFR2) in rat C6 glioma cells , 2008, Journal of neurochemistry.

[69]  H. van Steeg,et al.  Mechanisms of non-genotoxic carcinogens and importance of a weight of evidence approach. , 2009, Mutation research.

[70]  C. Gopinath,et al.  Mesovarian leiomyomas in the rat. , 1987, Environmental health perspectives.

[71]  M. Streiff,et al.  Inhibition of PDE4 phosphodiesterase activity induces growth suppression, apoptosis, glucocorticoid sensitivity, p53, and p21(WAF1/CIP1) proteins in human acute lymphoblastic leukemia cells. , 2002, Blood.

[72]  Z. Radi,et al.  Comparative pathophysiology, toxicology, and human cancer risk assessment of pharmaceutical-induced hibernoma. , 2013, Toxicology and applied pharmacology.

[73]  L. Sui,et al.  FOXO/TXNIP pathway is involved in the suppression of hepatocellular carcinoma growth by glutamate antagonist MK-801 , 2013, BMC Cancer.

[74]  P. Harvey.  Hypothesis Prolactin is tumorigenic to human breast: dispelling the myth that prolactin‐induced mammary tumors are rodent‐specific , 2012, Journal of applied toxicology : JAT.

[75]  D. J. Lewis,et al.  The Reproductive System , 1987 .

[76]  J. Avorn,et al.  Dopamine antagonists and the development of breast cancer. , 2002, Archives of general psychiatry.

[77]  K. Olejniczak,et al.  Evaluation of carcinogenicity studies of medicinal products for human use authorised via the European centralised procedure (1995-2009). , 2011, Regulatory toxicology and pharmacology : RTP.

[78]  J. Yatabe,et al.  Dopamine and Angiotensin Type 2 Receptors Cooperatively Inhibit Sodium Transport in Human Renal Proximal Tubule Cells , 2012, Hypertension.

[79]  J. Southgate,et al.  Effects of PPAR agonists on proliferation and differentiation in human urothelium. , 2008, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[80]  S. Karlsson,et al.  Initiating activity of the anti-estrogen tamoxifen, but not toremifene in rat liver. , 1997, Carcinogenesis.

[81]  A. Sjölander,et al.  CysLT 1 R Antagonists Inhibit Tumor Growth in a Xenograft Model of Colon Cancer , 2013 .

[82]  A. Temme,et al.  Silencing of selected glutamate receptor subunits modulates cancer growth. , 2011, Anticancer research.

[83]  J. W. van der Laan,et al.  Mechanisms of nongenotoxic carcinogenesis and assessment of the human hazard. , 2000, Regulatory toxicology and pharmacology : RTP.

[84]  C. Capen.  Mechanisms of Hormone-Mediated Carcinogenesis of the Ovary , 2004, Toxicologic pathology.

[85]  Y. Tokumitsu,et al.  Calcitonin induces IL-6 production via both PKA and PKC pathways in the pituitary folliculo-stellate cell line. , 2001, Endocrinology.

[86]  R. Stephens,et al.  Gastric ECL-cell hyperplasia produces enhanced basal and stimulated gastric acid output but not gastric erosion formation in the rat. , 1997, General pharmacology.

[87]  A. Martelli,et al.  Update on genotoxicity and carcinogenicity testing of 472 marketed pharmaceuticals. , 2009, Mutation research.

[88]  E. Larson,et al.  Acute, subacute and chronic toxicity/Carcinogenicity of lofexidine. , 1982, Arzneimittel-Forschung.

[89]  M. Woodward,et al.  The post hoc use of randomised controlled trials to explore drug associated cancer outcomes: methodological challenges. , 2013, Current drug safety.

[90]  L. Bernstein,et al.  Comparison of target organs of carcinogenicity for mutagenic and non-mutagenic chemicals. , 1993, Mutation research.

[91]  A. Hofman,et al.  Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis , 2015, Diabetologia.

[92]  P. Bugelski,et al.  Critical Review of Preclinical Approaches to Evaluate the Potential of Immunosuppressive Drugs to Influence Human Neoplasia , 2010, International journal of toxicology.

[93]  F. Sistare,et al.  An Evaluation of Chronic 6- and 12-Month Rat Toxicology Studies as Predictors of 2-Year Tumor Outcome , 2010, Veterinary pathology.

[94]  M. Pufall.  Glucocorticoids and Cancer. , 2015, Advances in experimental medicine and biology.

[95]  J. P. Van Oosterhout,et al.  The utility of two rodent species in carcinogenic risk assessment of pharmaceuticals in Europe. , 1997, Regulatory toxicology and pharmacology : RTP.

[96]  K. Netter,et al.  Effects of propionic acid and pravastatin on HMG-CoA reductase activity in relation to forestomach lesions in the rat. , 1996, Pharmacology & toxicology.

[97]  Yi Li,et al.  Differential regulation of bladder cancer growth by various glucocorticoids: corticosterone and prednisone inhibit cell invasion without promoting cell proliferation or reducing cisplatin cytotoxicity , 2014, Cancer Chemotherapy and Pharmacology.

[98]  R M Sharpe,et al.  Rodent Leydig cell tumorigenesis: a review of the physiology, pathology, mechanisms, and relevance to humans. , 1999, Critical reviews in toxicology.

[99]  P. Newberne,et al.  Lack of carcinogenicity of oxprenolol, a beta-adrenergic blocking agent. , 1977, Toxicology and applied pharmacology.

[100]  R. Ramsay,et al.  New Insights on COX-2 in Chronic Inflammation Driving Breast Cancer Growth and Metastasis , 2015, Journal of Mammary Gland Biology and Neoplasia.

[101]  A. Tischler.  The Rat Adrenal Medulla , 1989, Toxicologic pathology.

[102]  K. Ramana,et al.  Inhibition of aldose reductase prevents colon cancer metastasis. , 2011, Carcinogenesis.

[103]  A. Hofman,et al.  Verapamil is associated with an increased risk of cancer in the elderly: the Rotterdam study. , 2003, European journal of cancer.

[104]  M. Rogawski,et al.  New molecular targets for antiepileptic drugs: α2δ, SV2A, and Kv7/KCNQ/M potassium channels , 2008 .

[105]  C Helma,et al.  Data quality in predictive toxicology: reproducibility of rodent carcinogenicity experiments. , 2001, Environmental health perspectives.

[106]  L. Luttrell,et al.  5-HT2A Receptor Induces ERK Phosphorylation and Proliferation through ADAM-17 Tumor Necrosis Factor-α-converting Enzyme (TACE) Activation and Heparin-bound Epidermal Growth Factor-like Growth Factor (HB-EGF) Shedding in Mesangial Cells* , 2006, Journal of Biological Chemistry.

[107]  M. Zarrindast,et al.  Study of 5HT3 and HT4 receptor expression in HT29 cell line and human colon adenocarcinoma tissues. , 2010, Archives of Iranian medicine.

[108]  C. Gopinath,et al.  The Urinary System , 2014 .

[109]  A. Tischler,et al.  Acute stimulation of chromaffin cell proliferation in the adult rat adrenal medulla. , 1988, Laboratory investigation; a journal of technical methods and pathology.

[110]  Staffan Khan,et al.  Breast cancer risk and use of calcium channel blockers using Swedish population registries. , 2014, JAMA internal medicine.

[111]  S. Hamilton,et al.  Sporadic fundic gland polyps: common gastric polyps arising through activating mutations in the beta-catenin gene. , 2001, The American journal of pathology.

[112]  A. Tischler,et al.  The Rat Adrenal Medulla. II. Proliferative Lesions , 1988 .

[113]  Richard E. White,et al.  Rapid Suppression of Plasma Testosterone Levels and Tumor Growth in the Dunning Rat Model Treated with Degarelix, a New Gonadotropin-Releasing Hormone Antagonist , 2007, Journal of Pharmacology and Experimental Therapeutics.

[114]  S. Cohen.  An enhanced 13-week bioassay: an alternative to the 2-year bioassay to screen for human carcinogenesis. , 2009, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[115]  R. Woutersen,et al.  Influence of cholecystokinin antagonist on the effects of cholecystokinin and bombesin on azaserine-induced lesions in rat pancreas. , 1989, Gastroenterology.

[116]  Samuel M. Cohen,et al.  Urothelial Carcinogenesis in the Urinary Bladder of Male Rats Treated with Muraglitazar, a PPARα/γ Agonist: Evidence for Urolithiasis as the Inciting Event in the Mode of Action , 2006, Toxicologic pathology.

[117]  Lorna Ewart,et al.  A peripherally restricted P2Y12 receptor antagonist altered rat tumor incidences with no human relevance: Mode of action consistent with dopamine agonism , 2014, Toxicology reports.

[118]  G. Dockray,et al.  Gastrin: old hormone, new functions , 2004, Pflügers Archiv.

[119]  V. Petrozza,et al.  M2muscarinic receptors inhibit cell proliferation and migration in urothelial bladder cancer cells , 2014, Cancer biology & therapy.

[120]  J. Seong,et al.  Apoptotic Death of Prostate Cancer Cells by a Gonadotropin-Releasing Hormone-II Antagonist , 2014, PloS one.

[121]  S. Karlsson,et al.  A two-year dietary carcinogenicity study of the antiestrogen toremifene in Sprague-Dawley rats. , 1996, Drug and chemical toxicology.

[122]  R. Sigler,et al.  Gabapentin-induced mitogenic activity in rat pancreatic acinar cells. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[123]  Chao-yuan Huang,et al.  Role of D2 dopamine receptor in adrenal cortical cell proliferation and aldosterone-producing adenoma tumorigenesis. , 2014, Journal of molecular endocrinology.