Generic placeholder image

Cardiovascular & Hematological Agents in Medicinal Chemistry


ISSN (Print): 1871-5257
ISSN (Online): 1875-6182

Review Article

A Patent Review on Cardiotoxicity of Anticancerous Drugs

Author(s): Renu Bhadana and Vibha Rani*

Volume 22, Issue 1, 2024

Published on: 22 March, 2023

Page: [28 - 39] Pages: 12

DOI: 10.2174/1871525721666230120155734

Price: $65


Chemotherapy-induced cardiotoxicity is an increasing concern and it is critical to avoid heart dysfunction induced by medications used in various cancers. Dysregulated cardiomyocyte homeostasis is a critical phenomenon of drug-induced cardiotoxicity, which hinders the cardiac tissue's natural physiological function. Drug-induced cardiotoxicity is responsible for various heart disorders such as myocardial infarction, myocardial hypertrophy, and arrhythmia, among others. Chronic cardiac stress due to drug toxicity restricts the usage of cancer medications. Anticancer medications can cause a variety of adverse effects, especially cardiovascular toxicity. This review is focused on anticancerous drugs anthracyclines, trastuzumab, nonsteroidal anti-inflammatory medications (NSAIDs), and immune checkpoint inhibitors (ICI) and associated pathways attributed to the drug-induced cardiotoxicity. Several factors responsible for enhanced cardiotoxicity are age, gender specificity, diseased conditions, and therapy are also discussed. The review also highlighted the patents assigned for different methodologies involved in the assessment and reducing cardiotoxicity. Recent advancements where the usage of trastuzumab and bevacizumab have caused cardiac dysfunction and their effects alone or in combination on cardiac cells are explained. Extensive research on patents associated with protection against cardiotoxicity has shown that chemicals like bis(dioxopiperazine)s and manganese compounds were cardioprotective when combined with other selected anticancerous drugs. Numerous patents are associated with druginduced toxicity, prevention, and diagnosis, that may aid in understanding the current issues and developing novel therapies with safer cardiovascular outcomes. Also, the advancements in technology and research going on are yet to be explored to overcome the present issue of cardiotoxicity with the development of new drug formulations.

Keywords: Anticancerous drugs, cardiotoxicity, cell death, chemotherapy, apoptosis, patent.

Graphical Abstract
Quinn, T.A.; Kohl, P. Cardiac mechano-electric coupling: Acute effects of mechanical stimulation on heart rate and rhythm. Physiol. Rev., 2021, 101(1), 37-92.
[] [PMID: 32380895]
Vejpongsa, P.; Yeh, E.T.H. Prevention of anthracycline-induced cardiotoxicity: Challenges and opportunities.. J. Am. Coll. Cardiol., 2014, 64(9), 938-945.
[] [PMID: 25169180]
Zheng, P.P.; Li, J.; Kros, J.M. Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research-practice gaps, challenges, and insights. Med. Res. Rev., 2018, 38(1), 325-376.
[] [PMID: 28862319]
Niedrig, D.; Maechler, S.; Hoppe, L.; Corti, N.; Kovari, H.; Russmann, S. Drug safety of macrolide and quinolone antibiotics in a tertiary care hospital: Administration of interacting co-medication and QT prolongation. Eur. J. Clin. Pharmacol., 2016, 72(7), 859-867.
[] [PMID: 27023463]
Ai, D.; Banchs, J.; Owusu-Agyemang, P.; Cata, J.P. Chemotherapy-induced cardiovascular toxicity: Beyond anthracyclines. Minerva Anestesiol., 2014, 80(5)
[PMID: 24122036]
Dadson, K.; Calvillo-Argüelles, O.; Thavendiranathan, P.; Billia, F. Anthracycline-induced cardiomyopathy: Cellular and molecular mechanisms. Clin. Sci. (Lond.), 2020, 134(13), 1859-1885.
[] [PMID: 32677679]
Muslin, A.J. MAPK signalling in cardiovascular health and disease: Molecular mechanisms and therapeutic targets. Clin. Sci. (Lond.), 2008, 115(7), 203-218.
[] [PMID: 18752467]
Morelli, M.B.; Bongiovanni, C.; Da Pra, S.; Miano, C.; Sacchi, F.; Lauriola, M.; D’Uva, G. Cardiotoxicity of Anticancer Drugs: Molecular Mechanisms and Strategies for Cardioprotection. Front. Cardiovasc. Med., 2022, 9, 847012.
[] [PMID: 35497981]
Martins-Teixeira, M.B.; Carvalho, I. Antitumour Anthracyclines: Progress and Perspectives. ChemMedChem, 2020, 15(11), 933-948.
[] [PMID: 32314528]
Cardinale, D.; Colombo, A.; Bacchiani, G.; Tedeschi, I.; Meroni, C.A.; Veglia, F.; Civelli, M.; Lamantia, G.; Colombo, N.; Curigliano, G.; Fiorentini, C.; Cipolla, C.M. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation, 2015, 131(22), 1981-1988.
[] [PMID: 25948538]
Narezkina, A.; Narayan, H.K.; Zemljic-Harpf, A.E. Molecular mechanisms of anthracycline cardiovascular toxicity. Clin. Sci. (Lond.), 2021, 135(10), 1311-1332.
[] [PMID: 34047339]
Varricchi, G.; Ameri, P.; Cadeddu, C.; Ghigo, A.; Madonna, R.; Marone, G.; Mercurio, V.; Monte, I.; Novo, G.; Parrella, P.; Pirozzi, F.; Pecoraro, A.; Spallarossa, P.; Zito, C.; Mercuro, G.; Pagliaro, P.; Tocchetti, C.G. Antineoplastic drug-induced cardiotoxicity: A redox perspective. Front. Physiol., 2018, 9, 167.
[] [PMID: 29563880]
Gianni, L.; Eiermann, W.; Semiglazov, V.; Lluch, A.; Tjulandin, S.; Zambetti, M.; Moliterni, A.; Vazquez, F.; Byakhov, M.J.; Lichinitser, M.; Climent, M.A.; Ciruelos, E.; Ojeda, B.; Mansutti, M.; Bozhok, A.; Magazzù, D.; Heinzmann, D.; Steinseifer, J.; Valagussa, P.; Baselga, J. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): Follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol., 2014, 15(6), 640-647.
[] [PMID: 24657003]
Sarosiek, T.; Morawski, P. Trastuzumab and its biosimilars. Pol. Merkuriusz Lek., 2018, 44(263), 253-257.
[PMID: 29813044]
Vivekanandhan, S.; Knutson, K.L. Resistance to Trastuzumab. Cancers (Basel), 2022, 14(20), 5115.
[] [PMID: 36291900]
Dokmanovic, M.; Wu, W.J. Trastuzumab-induced HER2 phosphorylation: Exploring the mechanisms and implications. Receptors Clin. Investig., 2014, 1.
Zhao, Y.; Sawyer, D.R.; Baliga, R.R.; Opel, D.J.; Han, X.; Marchionni, M.A.; Kelly, R.A. Neuregulins promote survival and growth of cardiac myocytes. Persistence of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes. J. Biol. Chem., 1998, 273(17), 10261-10269.
[] [PMID: 9553078]
Junttila, T.T.; Li, G.; Parsons, K.; Phillips, G.L.; Sliwkowski, M.X. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res. Treat., 2011, 128(2), 347-356.
[] [PMID: 20730488]
Junttila, T.T.; Akita, R.W.; Parsons, K.; Fields, C.; Lewis Phillips, G.D.; Friedman, L.S.; Sampath, D.; Sliwkowski, M.X. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell, 2009, 15(5), 429-440.
[] [PMID: 19411071]
Zhang, S.; Huang, W.C.; Li, P.; Guo, H.; Poh, S.B.; Brady, S.W.; Xiong, Y.; Tseng, L.M.; Li, S.H.; Ding, Z.; Sahin, A.A.; Esteva, F.J.; Hortobagyi, G.N.; Yu, D. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat. Med., 2011, 17(4), 461-469.
[] [PMID: 21399647]
Onitilo, A.A.; Engel, J.M.; Stankowski, R.V. Cardiovascular toxicity associated with adjuvant trastuzumab therapy: Prevalence, patient characteristics, and risk factors. Ther. Adv. Drug Saf., 2014, 5(4), 154-166.
[] [PMID: 25083270]
Hasbullah, J.S.; Scott, E.N.; Bhavsar, A.P.; Gunaretnam, E.P.; Miao, F.; Soliman, H.; Carleton, B.C.; Ross, C.J.D. All-trans retinoic acid (ATRA) regulates key genes in the RARG-TOP2B pathway and reduces anthracycline-induced cardiotoxicity. PLoS One, 2022, 17(11), e0276541.
[] [PMID: 36331922]
Vejpongsa, P.; Yeh, E.T.H. Prevention of anthracycline-induced cardiotoxicity: Challenges and opportunities.. J. Am. Coll. Cardiol., 2014, 64(9), 938-945.
[] [PMID: 25169180]
Jiang, J.; Mohan, N.; Endo, Y.; Shen, Y.; Wu, W.J. Type IIB DNA topoisomerase is downregulated by trastuzumab and doxorubicin to synergize cardiotoxicity. Oncotarget, 2018, 9(5), 6095-6108.
[] [PMID: 29464058]
Yu, A.F.; Singh, J.C.; Wang, R.; Liu, J.E.; Eaton, A.; Oeffinger, K.C.; Steingart, R.M.; Hudis, C.A.; Dang, C.T. Cardiac safety of dual anti‐HER2 therapy in the neoadjuvant setting for treatment of HER2‐positive breast cancer. Oncologist, 2017, 22(6), 642-647.
[] [PMID: 28341761]
Poovassery, J.S.; Kang, J.C.; Kim, D.; Ober, R.J.; Ward, E.S. Antibody targeting of HER2/HER3 signaling overcomes heregulin-induced resistance to PI3K inhibition in prostate cancer. Int. J. Cancer, 2015, 137(2), 267-277.
[] [PMID: 25471734]
Berecz, T.; Yiu, A.; Vittay, O.; Orsolits, B.; Mioulane, M.; Remedios, C.G.; Ketteler, R.; Merkely, B.; Apáti, Á.; Harding, S.E.; Hellen, N.; Foldes, G. Transcriptional co‐activators YAP1–TAZ of Hippo signalling in doxorubicin‐induced cardiomyopathy. ESC Heart Fail., 2022, 9(1), 224-235.
[] [PMID: 34931757]
Scheuer, W.; Friess, T.; Burtscher, H.; Bossenmaier, B.; Endl, J.; Hasmann, M. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res., 2009, 69(24), 9330-9336.
[] [PMID: 19934333]
Bindu, S.; Mazumder, S.; Bandyopadhyay, U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem. Pharmacol., 2020, 180, 114147.
[] [PMID: 32653589]
Bombardier, C.; Laine, L.; Reicin, A.; Shapiro, D.; Burgos-Vargas, R.; Davis, B.; Day, R.; Ferraz, M.B.; Hawkey, C.J.; Hochberg, M.C.; Kvien, T.K.; Schnitzer, T.J. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N. Engl. J. Med., 2000, 343(21), 1520-1528. 2, 1528.
[] [PMID: 11087881]
Nussmeier, N.A.; Whelton, A.A.; Brown, M.T.; Langford, R.M.; Hoeft, A.; Parlow, J.L.; Boyce, S.W.; Verburg, K.M. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N. Engl. J. Med., 2005, 352(11), 1081-1091.
[] [PMID: 15713945]
Lyon, A.R.; Yousaf, N.; Battisti, N.M.L.; Moslehi, J.; Larkin, J. Immune checkpoint inhibitors and cardiovascular toxicity. Lancet Oncol., 2018, 19(9), e447-e458.
[] [PMID: 30191849]
Mir, H.; Alhussein, M.; Alrashidi, S.; Alzayer, H.; Alshatti, A.; Valettas, N.; Mukherjee, S.D.; Nair, V.; Leong, D.P. Cardiac complications associated with checkpoint inhibition: A systematic review of the literature in an important emerging area. Can. J. Cardiol., 2018, 34(8), 1059-1068.
[] [PMID: 29980467]
Ji, C.; Roy, M.D.; Golas, J.; Vitsky, A.; Ram, S.; Kumpf, S.W.; Martin, M.; Barletta, F.; Meier, W.A.; Hooper, A.T.; Sapra, P.; Khan, N.K.; Finkelstein, M.; Guffroy, M.; Buetow, B.S. Myocarditis in cynomolgus monkeys following treatment with immune checkpoint inhibitors. Clin. Cancer Res., 2019, 25(15), 4735-4748.
[] [PMID: 31085720]
Johnson, D.B.; Balko, J.M.; Compton, M.L.; Chalkias, S.; Gorham, J.; Xu, Y.; Hicks, M.; Puzanov, I.; Alexander, M.R.; Bloomer, T.L.; Becker, J.R.; Slosky, D.A.; Phillips, E.J.; Pilkinton, M.A.; Craig-Owens, L.; Kola, N.; Plautz, G.; Reshef, D.S.; Deutsch, J.S.; Deering, R.P.; Olenchock, B.A.; Lichtman, A.H.; Roden, D.M.; Seidman, C.E.; Koralnik, I.J.; Seidman, J.G.; Hoffman, R.D.; Taube, J.M.; Diaz, L.A., Jr; Anders, R.A.; Sosman, J.A.; Moslehi, J.J. Fulminant myocarditis with combination immune checkpoint blockade. N. Engl. J. Med., 2016, 375(18), 1749-1755.
Lipshultz, S.E.; Lipsitz, S.R.; Mone, S.M.; Goorin, A.M.; Sallan, S.E.; Sanders, S.P.; Orav, E.J.; Gelber, R.D.; Colan, S.D. Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N. Engl. J. Med., 1995, 332(26), 1738-1744.
[] [PMID: 7760889]
Sorensen, K.; Levitt, G.; Sebag-Montefiore, D.; Bull, C.; Sullivan, I. Cardiac function in Wilms’ tumor survivors. J. Clin. Oncol., 1995, 13(7), 1546-1556.
[] [PMID: 7602343]
Hershman, D.L.; McBride, R.B.; Eisenberger, A.; Tsai, W.Y.; Grann, V.R.; Jacobson, J.S. Doxorubicin, cardiac risk factors, and cardiac toxicity in elderly patients with diffuse B-cell non-Hodgkin’s lymphoma. J. Clin. Oncol., 2008, 26(19), 3159-3165.
[] [PMID: 18591554]
Jain, D. Cardiotoxicity of doxorubicin and other anthracycline derivatives. J. Nucl. Cardiol., 2000, 7(1), 53-62.
[] [PMID: 10698235]
Biancaniello, T.; Meyer, R.A.; Wong, K.Y.; Sager, C.; Kaplan, S. Doxorubicin cardiotoxicity in children. J. Pediatr., 1980, 97(1), 45-50.
[] [PMID: 7381647]
Wilcox, N.S.; Rotz, S.J.; Mullen, M.; Song, E.J.; Ky Hamilton, B.; Moslehi, J.; Armenian, S.H.; Wu, J.C.; Rhee, J.W.; Ky, B. Sex-specific cardiovascular risks of cancer and its therapies. Circ. Res., 2022, 130(4), 632-651.
[] [PMID: 35175846]
Simek, S.; Lue, B.; Rao, A.; Ravipati, G.; Vallabhaneni, S.; Zhang, K.; Zaha, V.G.; Chandra, A. Gender differences in diagnosis, prevention, and treatment of cardiotoxicity in cardio-oncology. J. Clin. Med., 2022, 11(17), 5167.
[] [PMID: 36079097]
Felker, G.M.; Thompson, R.E.; Hare, J.M.; Hruban, R.H.; Clemetson, D.E.; Howard, D.L.; Baughman, K.L.; Kasper, E.K. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N. Engl. J. Med., 2000, 342(15), 1077-1084.
[] [PMID: 10760308]
Mann, D.L. Mechanisms and models in heart failure: A combinatorial approach. Circulation, 1999, 100(9), 999-1008.
[] [PMID: 10468532]
Drímal, J.; Zúrová-Nedelcevová, J.; Knezl, V.; Sotníková, R.; Navarová, J. Cardiovascular toxicity of the first line cancer chemotherapeutic agents: Doxorubicin, cyclophosphamide, streptozotocin and bevacizumab. Neuroendocrinol. Lett., 2006, 27(Suppl. 2), 176-179.
[PMID: 17159809]
Pegram, M.; Hsu, S.; Lewis, G.; Pietras, R.; Beryt, M.; Sliwkowski, M.; Coombs, D.; Baly, D.; Kabbinavar, F.; Slamon, D. Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene, 1999, 18(13), 2241-2251.
[] [PMID: 10327070]
Piccart-Gebhart, M.J.; Procter, M.; Leyland-Jones, B.; Goldhirsch, A.; Untch, M.; Smith, I.; Gianni, L.; Baselga, J.; Bell, R.; Jackisch, C.; Cameron, D.; Dowsett, M.; Barrios, C.H.; Steger, G.; Huang, C.S.; Andersson, M.; Inbar, M.; Lichinitser, M.; Láng, I.; Nitz, U.; Iwata, H.; Thomssen, C.; Lohrisch, C.; Suter, T.M.; Rüschoff, J.; Sütő, T.; Greatorex, V.; Ward, C.; Straehle, C.; McFadden, E.; Dolci, M.S.; Gelber, R.D. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med., 2005, 353(16), 1659-1672.
[] [PMID: 16236737]
Sidorenko, J.S.; Sycheva, E.A.; Maksimova, N.A. Method for producing ultrasonic antracycline- induced cardiotoxicity evaluation in oncological patients. Russian Patent 2,225,166, 2004.
Bitter, H.M.L.; Kolaja, K.L.; Dhaw, P.; Uppal, H.; Gonzaludo, N. Prediction of cardiotoxicity. U.S. Patent 20,110,212,461, 2011.
Bacus, S.S. Methods for predicting cardiac toxicity. U.S. Patent 20,130,288,285, 2013.
Deichmann, O.D.; Fang, Y.; Ferrie, A.M.; Hu, H.; Wu, Q. Label free method for assessing chemical cardiotoxicity. U.S Patent 2,014,078,646, 2014.
Carleton, B.; Hayden, M.R.; Ross, C.J.; Aminkeng, F. Retinoic acid receptor gamma (RARG) gene polymorphisms predictive of Anthracycline-induced cardiotoxicity (ACT). Canadian Patent 2,911,709, 2016.
Roche, B.M.; Henderson, K.A. Use of 31p NMR spectroscopy of whole heart energetics for detection of drug-induced cardiotoxicity. U.S. Patent 9,393,324, 2016.
Yasuda, K.; Kaneko, T.; Nomura, F. Method and apparatus for testing cardiotoxicity and evaluating cardiomyocytes. U.S. Patent 9,447,447, 2016.
Teplyakov, A.T.; Grakova, E.V.; Shilov, S.N.; Berezikova, E.N.; Popova, A.A.; Neupokoeva, M.N. Method for predicting development of cardiotoxicity in patients with breast cancer within 12 months after chemotherapy with antracyclic drugs. RU Patent 2,680,139, 2019.
Teplyakov, A.T.; Grakova, E.V.; Shilov, S.N.; Berezikova, E.N.; Popova, A.A.; Neupokoeva, M.N.; Kopeva, K.V. Method for prediction of anthracycline-induced cardiotoxicity in women with breast cancer. R. U. Patent 2,714,683, 2020.
Coulombe, K.L.K.; Rupert, C.E.; Kofron, C.M.; Choi, B.R.; Kim, T.; Mende, U. A human in vitro cardiotoxicity model. U.S. Patent 2,020,232,436, 2020.
Speyer, J.L.; Muggia, F.M.; Green, M.D. Reduction of anthracycline-induced cardiotoxicity. U.S. Patent 5,744,455, 1998.
Towart, R.; Karlsson, J.O.G.; Jynge, P. Reduction of cardiotoxicity of an antitumor agent using manganese compound. Australian Patent 720,570, 2000.
Sreedhara, A.; Lukas, C.A.; Christina, H.D.T.P.; Mark, C.B.; Emma, L.C.; Zephania, W.K.G.; Lada, M.; Jayantha, R.; Graham, A.R.; Ru, A.W. Use of HER2-dimerization inhibitor pertuzumab and products containing pertuzumab. Japanese Patent 2,020,090,507, 2012.
Jay, S.M.; Griffith, L.G.; Lee, R.T. Neuregulin dimer for an ErbB/HER receptor for use in reducing cardiotoxicity. European Patent 2,555,788, 2017.
Armstrong, C.G.; Kim, K.J.; Pham, L.M.L.; Park, E.; Zhong, Z.; Huang, G. Pharmaceutical composition and methods for countering chemotherapy-induced cardiotoxicity. U.S Patent 2,017,136,774, 2017.
Armstrong, C.G.; Kim, K.J.; Pham, L.M.L.; Park, E.; Zhong, Z.; Huang, G.; W, J.C.; Elmer, S.P.; Visuthikraisee, V.; Cadag, E.M.G.; Freeman, T.B.; Lum, P.Y. Pharmaceutical’s compositions and methods for controlling cardiotoxicity caused by chemotherapy. Russian Patent 2,743,433, 2021.
Asp, B.; Ogden, A.; Miller, L.; Podesta, A. Method for the treatment of cardiotoxicity induced by antitumor compounds. U.S. patent 20,040,258,692, 2004.
Wang, C.; Lue, Y.; Swerdloff, R. Methods for reducing cardiotoxicity from chemotherapy by administering humanin analogue compositions. U.S. patent 10,792,331, 2020.
Freudenberger, R. Use of oxypurinol as an inhibitor of antineoplastic agent-induced cardiotoxicity. U.S. patent 20,080,039,408, 2008.
Krapcho, A.P.; Hacker, M.P.; Cavalletti, E. 6,9-Bisl(2-aminoethyl) aminobenzo gisoquinoline-5,10. dione dimaleate; an azaanthracenedione with reduced cardiotoxicity. U.S. patent 5,587,382, 1996.
Blinova, K.; Dang, Q.; Millard, D.; Smith, G.; Pierson, J.; Guo, L.; Brock, M.; Lu, H. R.; Kraushaar, U.; Zeng, H.; Shi, H.; Zhang, X.; Sawada, K.; Osada, T.; Kanda, Y.; Sekino, Y.; Pang, L.; Feaster, T.K.; Kettenhofen, R.; Stockbridge, N.; Strauss, D.G.; Gintant, G. International multisite study of human-induced pluripotent stem cell-derived cardiomyocytes for drug proarrhythmic potential assessment. Cell reports, 2018, 24(13), 3582-3592.
Golforoush, P.A.; Narasimhan, P.; Chaves-Guerrero, P.P.; Lawrence, E.; Newton, G.; Yan, R.; Harding, S.E.; Perrior, T.; Chapman, K.L.; Schneider, M.D. Selective protection of human cardiomyocytes from anthracycline cardiotoxicity by small molecule inhibitors of MAP4K4. Sci. Rep., 2020, 10(1), 12060.
[] [PMID: 32694738]
Tsai, J.; Lam, J.; Pike, N.K.; Armstrong, C.G. Modulation of druginduced cardiotoxicity. U.S. Patent 2,016,191,316, 2016.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy