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Critical Reviews™ in Oncogenesis
SJR: 0.631 SNIP: 0.503 CiteScore™: 2

ISSN 印刷: 0893-9675
ISSN オンライン: 2162-6448

Critical Reviews™ in Oncogenesis

DOI: 10.1615/CritRevOncog.2019031641
pages 199-212

Gemcitabine: A Review of Chemoresistance in Pancreatic Cancer

Deepika Sarvepalli
Department of Internal Medicine, AdventHealth, Orlando, FL 32804
Mamoon Ur Rashid
Department of Gastroenterology, Cleveland Clinic, Weston, Florida; Department of Internal Medicine, AdventHealth, Orlando, FL 32804
Asad Ur Rahman
Abington Hospital−Jefferson Health, Abington, Pennsylvania
Waqas Ullah
Khyber Teaching Hospital, Peshawar, Khyber Pakhtunkhwa, Pakistan; Abington Hospital - Jefferson Health, Abington, PA 19001, USA
Ishtiaq Hussain
Abington Hospital−Jefferson Health, Abington, Pennsylvania; Department of Gastroenterology, Cleveland Clinic, Weston, FL 33331
Badar Hasan
Abington Hospital−Jefferson Health, Abington, Pennsylvania
Sundas Jehanzeb
Khyber Teaching Hospital, Peshawar, Khyber Pakhtunkhwa 25000, Pakistan
Abdul Kareem Khan
Department of Internal Medicine, AdventHealth, Orlando, FL 32804
Akriti Gupta Jain
Department of Internal Medicine, AdventHealth, Orlando, Florida
Neelam Khetpal
Department of Internal Medicine, AdventHealth, Orlando, Florida
Sarfraz Ahmad
Department of Gynecologic Oncology, AdventHealth Cancer Institute, Orlando, FL 32804

要約

Pancreatic ductal adenocarcinoma, an exocrine tumor, is the most common type of cancer of the pancreas and one of the top five most prominent causes of cancer-associated mortality worldwide. The survival rate for pancreatic cancer is sadly less than 8%. The high fatality rate is partly related to late diagnosis and partly to the aggressive nature of malignant cells that disseminate to nearby tissues at an early stage of the disease, making treatment difficult. Available treatment choices consist of both medical and surgical: removal of the tumor, use of various medications like chemotherapeutic drugs and immunotherapeutic agents, radiation therapy, and targeted drug therapy. Since most patients suffer from advanced cancer at the time of diagnosis, chemotherapy becomes the primary therapeutic option in such cases. Drugs like Gemcitabine, Abraxane, FOLFIRINOX, and newer combination therapies are all effective in management, either curatively or palliatively. However, chemoresistance poses a significant challenge. Several factors, both intrinsic and acquired, are involved in drug resistance. Here, we review the mechanism of action of the first-line chemotherapy drugs in pancreatic cancer and various factors associated with cancer chemoresistance.

参考

  1. Garrido-Laguna I, Hidalgo M. Pancreatic cancer: from state-of-the-art treatments to promising novel therapies. Nature Rev Clin Oncol. 2015 Jun;12(6):319-334.

  2. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014 Jun 1;74(11):2913-21.

  3. Sohn TA, Yeo CJ, Cameron JL, Koniaris L, Kaushal S, Abrams RA, Sauter PK, Coleman J, Hruban RH, Lillemoe KD. Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastro Surg. 2000 Nov 1;4(6):567-79.

  4. Adamska A, Domenichini A, Falasca M. Pancreatic ductal adenocarcinoma: current and evolving therapies. Int J Mol Sci. 2017 Jul;18(7):1338.

  5. Huang P, Chubb S, Hertel LW, Grindey GB, Plunkett W. Action of 2', 2'-difluorodeoxycytidine on DNA synthesis. Cancer Res. 1991 Nov 15;51(22):6110-7.

  6. Gandhi V, Plunkett W. Modulatory activity of 2', 2'-difluorodeoxycytidine on the phosphorylation and cytotoxicity of arabinosyl nucleosides. Cancer Res. 1990 Jun 15;50(12):3675-80.

  7. Mini E, Nobili SF, Caciagli BF, Landini I, Mazzei T. Cellular pharmacology of gemcitabine. Annals Oncol. 2006 May 1;17(Suppl 5):v7-12.

  8. Fukunaga AK, Marsh S, Murry DJ, Hurley TD, McLeod HL. Identification and analysis of single-nucleotide polymorphisms in the gemcitabine pharmacologic pathway. Pharmacogenom J. 2004 Sep;4(5):307.

  9. Young JD, Yao SY, Baldwin JM, Cass CE, Baldwin SA. The human concentrative and equilibrative nucleoside transporter families, SLC28 and SLC29. Mol Aspects Med. 2013 Apr 1;34(2-3):529-47.

  10. Heinemann V, Xu YZ, Chubb S, Sen A, Hertel LW, Grindey GB, Plunkett W. Cellular elimination of 2', 2'-difluorodeoxycytidine 5'-triphosphate: a mechanism of self-potentiation. Cancer Res. 1992 Feb 1;52(3):533-9.

  11. Burris HA, 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Christine Cripps M, Portenoy RK, Storniolo AM, Tarassoff P. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun 1;15(6):2403-13.

  12. Rothenberg ML, Moore MJ, Cripps MC, Andersen JS, Portenoy RK, Burriss III HA, Green MR, Tarassoff PG, Brown TD, Casper ES, Storniolo AM. A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Annals Oncol. 1996 Apr 1;7(4):347-53.

  13. Di Costanzo F, Carlini P, Doni L, Massidda B, Mattioli R, Iop A, Barletta E, Moscetti L, Recchia F, Tralongo P, Gasperoni S. Gemcitabine with or without continuous infusion 5-FU in advanced pancreatic cancer: a randomised phase II trial of the Italian oncology group for clinical research (GOIRC). British J Cancer. 2005 Jul;93(2):185.

  14. Di Marco M, Di Cicilia R, Macchini M, Nobili E, Vecchiarelli S, Brandi G, Biasco G. Metastatic pancreatic cancer: is gemcitabine still the best standard treatment?. Oncol Rep. 2010 May 1;23(5):1183-92.

  15. Min YJ, Joo KR, Park NH, Yun TK, Nah YW, Nam 24. CW, Park JH. Gemcitabine therapy in patients with advanced pancreatic cancer. Korean J Internal Med. 2002 Dec;17(4):259-62.

  16. Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol. 2005 Jun 1;6(6):369-76.

  17. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007 May 20;25(15):1960-6.

  18. Boeck S, Hoehler T, Seipelt G, Mahlberg R, Wein A, Hochhaus A, Boeck HP, Schmid B, Kettner E, Stauch M, Lordick F. Capecitabine plus oxaliplatin (CapOx) versus capecitabine plus gemcitabine (CapGem) versus gemcitabine plus oxaliplatin (mGemOx): final results of a multicenter randomized phase II trial in advanced pancreatic cancer. Annals Oncol. 2007 Oct 24;19(2):340-7.

  19. Fine RL, Fogelman DR, Schreibman SM, Desai M, Sherman W, Strauss J, Guba S, Andrade R, Chabot J. The gemcitabine, docetaxel, and capecitabine (GTX) regimen for metastatic pancreatic cancer: a retrospective analysis. Cancer Chemother Pharmacol. 2008 Jan 1;61(1):167-75.

  20. Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, Andre T, Zaniboni A, Ducreux M, Aitini E, Taieb J, Faroux R. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol. 2005 May 20;23(15):3509-16.

  21. Colucci G, Giuliani F, Gebbia V, Biglietto M, Rabitti P, Uomo G, Cigolari S, Testa A, Maiello E, Lopez M. Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: A prospective, randomized phase III study of the Gruppo Oncologico dell'Italia Meridionale. Cancer. 2002 Feb 15;94(4):902-10.

  22. Ychou M, Conroy T, Seitz JF, Gourgou S, Hua A, Mery-Mignard D, Kramar A. An open phase I study assessing the feasibility of the triple combination: oxaliplatin plus irinotecan plus leucovorin/5-fluorouracil every 2 weeks in patients with advanced solid tumors. Annals Oncol. 2003 Mar 1;14(3):481-9.

  23. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, Bennouna J. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. New England J Med. 2011 May 12;364(19):1817-25.

  24. Peddi PF, Lubner S, McWilliams R, Tan BR, Picus J, Sorscher SM, Suresh R, Lockhart AC, Wang J, Menias C, Gao F. Multi-institutional experience with FOLFIRINOX in pancreatic adenocarcinoma. J Pancreas. 2012 Sep 10;13(5):497.

  25. Mahaseth H, Brutcher E, Kauh J, Hawk N, Kim S, Chen Z, Kooby DA, Maithel SK, Landry J, El-Rayes BF. Modified FOLFIRINOX regimen with improved safety and maintained efficacy in pancreatic adenocarcinoma. Pancreas. 2013 Nov 1;42(8):1311-5.

  26. Stinchcombe TE. Nanoparticle albumin-bound paclitaxel: a novel Cremphor-EL-free formulation of paclitaxel. Nanomedicine (Lond). 2007 Aug;2(4):415-23.

  27. Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011 Dec 1;29(34):4548.

  28. Thota R, Pauff JM, Berlin JD. Treatment of metastatic pancreatic adenocarcinoma: a review. Oncology. 2014 Jan 15;28(1):70-74.

  29. Martin M, Andres J, Garcia Alfonso P, Ruperez AB, Martin Jimenez M. Nab paclitaxel plus gemcitabine as first line palliative chemotherapy in a patient with metastatic pancreatic cancer with Eastern Cooperative Oncology Group performance status of 2. Oncol Lett. 2016 Jul 1;12(1):727-30.

  30. Rueff J, Rodrigues AS. Cancer drug resistance: A brief overview from a genetic viewpoint. In: Cancer drug resistance. Molecular biology. New York, NY: Humana Press; 2016. p. 1-18.

  31. Szakacs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nature Rev Drug Discov. 2006 Mar;5(3):219-34.

  32. Wang Z, Li Y, Ahmad A, Banerjee S, Azmi AS, Kong D, Sarkar FH. Pancreatic cancer: understanding and overcoming chemoresistance. Nature Rev Gastroenterol Hepatol. 2011 Jan;8(1):27-33.

  33. Marechal R, Mackey JR, Lai R, Demetter P, Peeters M, Polus M, Cass CE, Young J, Salmon I, Deviere J, Van Laethem JL. Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma. Clin Cancer Res.2009 Apr 15;15(8):2913-9.

  34. Giovannetti E, Del Tacca M, Mey V, Funel N, Nannizzi S, Ricci S, Orlandini C, Boggi U, Campani D, Del Chiaro M, Iannopollo M. Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. Cancer Res. 2006 Apr 1;66(7):3928-35.

  35. Mackey JR, Mani RS, Selner M, Mowles D, Young JD, Belt JA, Crawford CR, Cass CE. Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. Cancer Res. 1998 Oct 1;58(19):4349-57.

  36. Andersson R, Aho U, Nilsson BI, Peters GJ, Pastor-Anglada M, Rasch W, Sandvold ML. Gemcitabine chemoresistance in pancreatic cancer: molecular mechanisms and potential solutions. Scandinavian J Gastroenterol. 2009 Jan 1;44(7):782-6.

  37. Bhutia YD, Hung SW, Patel B, Lovin D, Govindarajan R. CNT1 expression influences proliferation and chemosensitivity in drug-resistant pancreatic cancer cells. Cancer Res. 2011 Mar 1;71(5):1825-35.

  38. Chaturvedi P, Singh AP, Moniaux N, Senapati S, Chakraborty S, Meza JL, Batra SK. MUC4 mucin 48. potentiates pancreatic tumor cell proliferation, survival, and invasive properties and interferes with its interaction to extracellular matrix proteins. Mol Cancer Res. 2007 Apr 1;5(4):309-20.

  39. Bafna S, Kaur S, Momi N, Batra SK. Pancreatic cancer cells resistance to gemcitabine: the role of MUC4 mucin. 49. British J Cancer. 2009 0ct;101(7):1155-61.

  40. Skrypek N, Duchene B, Hebbar M, Leteurtre E, Van Seuningen I, Jonckheere N. The MUC4 mucin mediates gemcitabine resistance of human pancreatic cancer cells via the Concentrative Nucleoside Transporter family. Oncogene. 2013 Mar;32(13):171-23.

  41. Jonckheere N, Skrypek N, Merlin J, Dessein AF, Dumont P, Leteurtre E, Harris A, Desseyn JL, Susini C, Frenois F, Van Seuningen I. The mucin MUC4 and its membrane partner ErbB2 regulate biological properties of human CAPAN-2 pancreatic cancer cells via different signalling pathways. PLoS One. 2012 Feb 29;7(2):e32232.

  42. Skrypek N, Vasseur R, Vincent A, Duchene B, Van Seuningen I, Jonckheere N. The oncogenic receptor ErbB2 modulates gemcitabine and irinotecan/SN-38 chemoresistance of human pancreatic cancer cells via hCNT1 transporter and multidrug-resistance associated protein MRP-2. Oncotarget. 2015 May 10;6(13):10853-53.

  43. Nakano Y, Tanno S, Koizumi K, Nishikawa T, Nakamura K, Minoguchi M, Izawa T, Mizukami Y, Okumura T, Kohgo Y. Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells. British J Cancer. 2007 Feb;96(3):457-63.

  44. Funamizu N, Okamoto A, Kamata Y, Misawa T, Uwagawa T, Gocho T, Yanaga K, Manome Y. Is the resistance of gemcitabine for pancreatic cancer settled only by overexpression of deoxycytidine kinase?. Oncol Rep. 2010 Feb 1;23(2):471-5.

  45. Kroep JR, Loves WJ, Van Der Wilt CL, Alvarez E, Talianidis I, Boven E, Braakhuis BJ, Van Groeningen CJ, Pinedo HM, Peters GJ. Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity 1 supported by Eli Lilly & Co, International and The Netherlands. Mol Cancer Therap. 2002Apr 1;1(6):371-6.

  46. Sebastiani V, Ricci F, Rubio-Viquiera B, Kulesza P, Yeo CJ, Hidalgo M, Klein A, Laheru D, Iacobuzio-Donahue CA. Immunohistochemical and genetic evaluation of deoxycytidine kinase in pancreatic cancer: relationship to molecular mechanisms of gemcitabine resistance and survival. Clin Cancer Res. 2006 Apr 15;12(8):2492-7.

  47. Costantino CL, Witkiewicz AK, Kuwano Y, Cozzitorto JA, Kennedy EP, Dasgupta A, Keen JC, Yeo CJ, Gorospe M, Brody JR. The role of HuR in gemcitabine efficacy in pancreatic cancer: HuR Up-regulates the expression of the gemcitabine metabolizing enzyme deoxycytidine kinase. Cancer Res. 2009 Jun 1;69(11):4567-72.

  48. Williams TK, Costantino CL, Bildzukewicz NA, Richards NG, Rittenhouse DW, Einstein L, Cozzitorto JA, Keen JC, Dasgupta A, Gorospe M, Gonye GE. pp32 (ANP32A) expression inhibits pancreatic cancer cell growth and induces gemcitabine resistance by disrupting HuR binding to mRNAs. PLoS One. 2010 Nov 29;5(11):e15455.

  49. Shipley LA, Brown TJ, Cornpropst JD, Hamilton MA, Daniels WD, Culp HW. Metabolism and disposition of gemcitabine, and oncolytic deoxycytidine analog, in mice, rats, and dogs. Drug Metabol Disposition. 1992 Nov 1;20(6):849-55.

  50. Minami K, Shinsato Y, Yamamoto M, Takahashi H, Zhang S, Nishizawa Y, Tabata S, Ikeda R, Kawahara K, Tsujikawa K, Chijiiwa K. Ribonucleotide reductase is an effective target to overcome gemcitabine resistance in gemcitabine-resistant pancreatic cancer cells with dual resistant factors. J Pharmacol Sci. 2015 Mar 1;127(3):319-25.

  51. Bafna S, Kaur S, Momi N, Batra SK. Pancreatic cancer cells resistance to gemcitabine: the role of MUC4 mucin. British J Cancer. 2009 Oct;101(7):1155-61.

  52. Rose MG, Farrell MP, Schmitz JC. Thymidylate synthase: a critical target for cancer chemotherapy. Clin Colorectal Cancer. 2002 Feb 1;1(4):220-9.

  53. Komori S, Osada S, Yoshida K. Novel strategy with gemcitabine for advanced pancreatic cancer. ISRN Oncol. 2011 May 23;2011:936893.

  54. Nakai Y, Isayama H, Sasaki T, Sasahira N, Tsujino T, Toda N, Kogure H, Matsubara S, Ito Y, Togawa O, Arizumi T. A multicentre randomised phase II trial of gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer: GEMSAP study. British J Cancer. 2012 Jun;106(12):1934-39.

  55. Komori S, Osada S, Mori R, Matsui S, Sanada Y, Tomita H, Tokuyama Y, Takahashi T, Yamaguchi K, Yoshida K. Contribution of thymidylate synthase to gemcitabine therapy for advanced pancreatic cancer. Pancreas. 2010 Nov 1;39(8):1284-92.

  56. Locher KP. Structure and mechanism ofABC transporters. Curr Op Structural Biol. 2004 Aug 1;14(4):426-31.

  57. Linton KJ. Structure and function of ABC transporters. Physiology. 2007 Apr;22(2):122-30.

  58. Hyde SC, Emsley P, Hartshorn MJ, Mimmack MM, Gileadi U, Pearce SR, Gallagher MP, Gill DR, Hubbard RE, Higgins CF. Structural model ofATP-binding protein associated with cystic fibrosis, multidrug resistance and bacterial transport. Nature. 1990 Jul;346(6282):362-65.

  59. Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM. Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annual Rev Pharmacol Toxicol. 1999 Apr;39( 1):361-98.

  60. Albrecht C, Viturro E. The ABCA subfamily-gene and protein structures, functions and associated hereditary diseases. Pflugers Archiv-European J Physiol. 2007 Feb 73. 1;453(5):581-9.

  61. Takahashi K, Kimura Y, Nagata K, Yamamoto A, Matsuo M, Ueda K. ABC proteins: key molecules for lipid homeostasis. Med Mol Morphol. 2005 Mar 1;38(1):2-12.

  62. Dean M, Annilo T. Evolution of the ATP-binding cassette (ABC) transporter superfamily in vertebrates. Annual Rev Genom Hum Genet. 2005 Sep 22;6:123-42.

  63. Kruh GD, Belinsky MG. The MRP family of drug efflux pumps. Oncogene. 2003 Oct;22(47):7537-52.

  64. Hirohashi T, Suzuki H, Sugiyama Y. Characterization of the transport properties of cloned rat multidrug resistance-associated protein 3 (MRP3). J Bio Chem. 1999 May 21;274(21):15181-5.

  65. Kool M, Van Der Linden M, de Haas M, Scheffer GL, De Vree JM, Smith AJ, Jansen G, Peters GJ, Ponne N, Scheper RJ, Elferink RP. MRP3, an organic anion transporter able to transport anti-cancer drugs. Proc Natl Acad Sci. 1999 Jun 8;96(12):6914-9.

  66. Hagmann W, Jesnowski R, Lohr JM. Interdependence of gemcitabine treatment, transporter expression, and resistance in human pancreatic carcinoma cells. Neoplasia (New York, NY). 2010 Sep;12(9):740.

  67. Ueda K. ABC proteins protect the human body and maintain optimal health. Biosci Biotechnol Biochem. 2011 Mar 23;75(3):401-409.

  68. Giovannetti E, Funel N, Peters GJ, Del Chiaro M, Erozenci LA, Vasile E, Leon LG, Pollina LE, Groen A, Falcone A, Danesi R. MicroRNA-21 in pancreatic cancer: correlation with clinical outcome and pharmacologic aspects underlying its role in the modulation of gemcitabine activity. Cancer Res. 2010 Jun 1;70(11):4528-38.

  69. Wang Z, Li Y, Kong D, Banerjee S, Ahmad A, Azmi AS, Ali S, Abbruzzese JL, Gallick GE, Sarkar FH. Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res. 2009 Mar 15;69(6):2400-7.

  70. Gungor C, Zander H, Effenberger KE, Vashist YK, Kalinina T, Izbicki JR, Yekebas E, Bockhorn M. Notch signaling activated by replication stress-induced expression of midkine drives epithelial-mesenchymal transition and chemoresistance in pancreatic cancer. Cancer Res. 2011 Jul 15;71(14):5009-19.

  71. Ma J, Fang B, Zeng F, Ma C, Pang H, Cheng L, Shi Y, Wang H, Yin B, Xia J, Wang Z. Down-regulation of miR-223 reverses epithelial-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Oncotarget. 2015 Jan;6(3):1740-9.

  72. Apte MV, Park S, Phillips PA, Santucci N, Goldstein D, Kumar RK, Ramm GA, Buchler M, Friess H, McCarroll JA, Keogh G. Desmoplastic reaction in pancreatic cancer: role of pancreatic stellate cells. Pancreas. 2004 Oct 1;29(3):179-87.

  73. Apte MV, Haber PS, Darby SJ, Rodgers SC, McCaughan GW, Korsten MA, Pirola RC, Wilson JS. Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis. Gut. 1999 Apr 1;44(4):534-41.

  74. Chan DA, Giaccia AJ. Hypoxia, gene expression, and metastasis. Cancer Meta Rev. 2007 Jun 1;26(2):333-9.

  75. Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res. 2002 Jun 15;62(12):3387-94.

  76. Bailey JM, Swanson BJ, Hamada T, Eggers JP, Singh PK, Caffery T, Ouellette MM, Hollingsworth MA. Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin Cancer Res. 2008 Oct 1;14(19):5995-6004.

  77. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009 Jun 12;324(5933):1457-61.

  78. Khan S, Ebeling MC, Chauhan N, Thompson PA, Gara RK, Ganju A, Yallapu MM, Behrman SW, Zhao H, Zafar N, Singh MM. Ormeloxifene suppresses desmoplasia and enhances sensitivity of gemcitabine in pancreatic cancer. Cancer Res. 2015 Jun 1;75(11):2292-304.

  79. Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, Frese KK, Feig C, Nakagawa T, Caldwell ME, Zecchini HI, Lolkema MP. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut. 2013 Jan 1;62(1):112-20.

  80. Hingorani SR, Zheng L, Bullock AJ, Seery TE, Harris WP, Sigal DS, Braiteh F, Ritch PS, Zalupski MM, Bahary N, Oberstein PE. HALO 202: randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine versus nab-paclitaxel/gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma. J Clin Oncol. 2018 Feb 1;36(4):359-66.

  81. Ramanathan RK, McDonough S, Philip PA, Hingorani SR, Lacy J, Kortmansky JS, Thumar JR, Chiorean EG, Shields AF, Behl D, Mehan PT. A phase IB/II randomized study of mFOLFIRINOX (mFFOX)+pegylated recombinant human hyaluronidase (PEGPH20) versus mFFOX alone in patients with good performance status metastatic pancreatic adenocarcinoma (mPC): SWOG S1313 (NCT# 01959139). J Clin Oncol. 2018;36(4 Suppl):208-208. doi: 10.1200/JCO.2018.36.4_suppl.208 89.

  82. Madden JI. Infinity reports update from phase 2 study of saridegib plus gemcitabine in patients with metastatic pancreatic cancer. Infinity Pharm. 2012.

  83. Bachem MG, Schunemann M, Ramadani M, Siech M, Beger H, Buck A, Zhou S, Schmid-Kotsas A, Adler G. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology. 2005 Apr 1;128(4):907-21.

  84. Ohlund D, Handly-SantanaA, Biffi G, Elyada E,Almeida AS, Ponz-Sarvise M, Corbo V, Oni TE, Hearn SA, Lee EJ, Chio II. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exper Med. 2017 Mar 6;214(3):579-96.

  85. Solinas G, Germano G, Mantovani A, Allavena P. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leuk Biol. 2009 Nov;86(5):1065-73.

  86. Weizman N, Krelin Y, Shabtay-Orbach A, Amit M, Binenbaum Y, Wong RJ, Gil Z. Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase. Oncogene. 2014 Jul;33(29):3812-9.

  87. Mitchem JB, Brennan DJ, Knolhoff BL, Belt BA, Zhu Y, Sanford DE, Belaygorod L, Carpenter D, Collins L, Piwnica-Worms D, Hewitt S. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 2013 Feb 1;73(3):1128-41.

  88. Kuwada K, Kagawa S, Yoshida R, Sakamoto S, Ito A, Watanabe M, Ieda T, Kuroda S, Kikuchi S, Tazawa H, Fujiwara T. The epithelial-to-mesenchymal transition induced by tumor-associated macrophages confers chemoresistance in peritoneally disseminated pancreatic cancer. J Exper Clin Cancer Res. 2018 Dec;37(1):307.

  89. Zhang M, Yan L, Wang GJ, Jin R. Resistin effects on pancreatic cancer progression and chemoresistance are mediated through its receptors CAP1 and TLR4. J Cell Physiol. 2019 Jun;234(6):9457-66.

  90. Ireland L, Santos A, Ahmed MS, Rainer C, Nielsen SR, Quaranta V, Weyer-Czernilofsky U, Engle DD, Perez-Mancera PA, Coupland SE, Taktak A. Chemoresistance in pancreatic cancer is driven by stroma-derived insulin-like growth factors. Cancer Res. 2016 Dec 1;76(23):6851-63.

  91. Tape CJ, Ling S, Dimitriadi M, McMahon KM, Worboys JD, Leong HS, Norrie IC, Miller CJ, Poulogiannis G, Lauffenburger DA, J0rgensen C. Oncogenic KRAS regulates tumor cell signaling via stromal reciprocation. Cell. 2016 May 5;165(4):910-20.

  92. Ireland L, Santos A, Ahmed MS, Rainer C, Nielsen SR, Quaranta V, Weyer-Czernilofsky U, Engle DD, Perez-Mancera PA, Coupland SE, Taktak A. Chemoresistance in pancreatic cancer is driven by stroma-derived insulin-like growth factors. Cancer Res. 2016 Dec 1;76(23):6851-63.

  93. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. Cancer J Clin. 2015 Jan;65(1):5-29.

  94. Baxter R. A clinical study comparing acelarin with gemcitabine in patient with metastatic pancreatic carcinoma. ISRCTN Registry. 2015 (# NCT03610100).


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Krishna Patel, Maya Nair, Riyaz Basha, Sohail Siraj, Jamboor K. Vishwanatha, Chloe Smith
Noncoding RNAs (ncRNA) in Hepato Cancer: A Review
Journal of Environmental Pathology, Toxicology and Oncology, Vol.37, 2018, issue 1
Xiujuan Sun, Anshoo Malhotra
Lessons Learned from Gemcitabine: Impact of Therapeutic Carrier Systems and Gemcitabine’s Drug Conjugates on Cancer Therapy
Critical Reviews™ in Therapeutic Drug Carrier Systems, Vol.34, 2017, issue 1
Sathish Dyawanapelly, Animesh Kumar, Manish K. Chourasia
New Prospectives of Prostate Cancer Gene Therapy: Molecular Targets and Animal Models
Critical Reviews™ in Eukaryotic Gene Expression, Vol.11, 2001, issue 1-3
Chia-Ling Hsieh, Leland W. K. Chung