• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of gutGutCurrent TOCInstructions to authors
Gut. Aug 2001; 49(2): 251–262.
PMCID: PMC1728385

Interferon γ inhibits growth of human pancreatic carcinoma cells via caspase-1 dependent induction of apoptosis

Abstract

BACKGROUND AND AIMS—The poor prognosis of pancreatic cancer is partly due to resistance to a broad spectrum of apoptotic stimuli. To identify intact proapoptotic pathways of potential clinical relevance, we characterised the effects of interferon γ (IFN-γ) on growth and survival in human pancreatic cancer cells.
METHODS—IFN-γ receptor expression and signal transduction were examined by reverse transcriptase-polymerase chain reaction (RT-PCR), immunoprecipitation, western blot analysis, and transactivation assays. Effects on cell growth and survival were evaluated in terms of cell numbers, colony formation, cell cycle analysis, DNA fragmentation, and poly(ADP ribose) polymerase (PARP) cleavage.
RESULTS—All four pancreatic cancer cell lines examined expressed functional IFN-γ receptors and downstream effectors, including the putative tumour suppressor interferon regulatory factor 1 (IRF-1). IFN-γ treatment profoundly inhibited anchorage dependent and independent growth of pancreatic cancer cells. Cell cycle analyses revealed subdiploid cells suggesting apoptosis, which was confirmed by demonstration of DNA fragmentation and PARP cleavage. Time and dose dependency of apoptosis induction and growth inhibition correlated closely, identifying apoptosis as the main, if not exclusive, mechanism responsible for growth inhibition. Apoptosis was preceded by upregulation of procaspase-1 and accompanied by proteolytic activation. Furthermore, the caspase inhibitor z-vad-fmk completely prevented IFN-γ mediated apoptosis.
CONCLUSIONS—These results identify an intact proapoptotic pathway in pancreatic cancer cells and suggest that IRF-1 and/or procaspase-1 may represent potential therapeutic targets to be further explored.


Keywords: interferon γ; apoptosis; caspase-1;interferon regulatory factor; pancreatic cancer

Full Text

The Full Text of this article is available as a PDF (288K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Rubin BY, Gupta SL. Differential efficacies of human type I and type II interferons as antiviral and antiproliferative agents. Proc Natl Acad Sci U S A. 1980 Oct;77(10):5928–5932. [PMC free article] [PubMed]
  • Jia SF, Kleinerman ES. Antitumor activity of TNF-alpha, IL-1, and IFN-gamma against three human osteosarcoma cell lines. Lymphokine Cytokine Res. 1991 Aug;10(4):281–284. [PubMed]
  • Palumbo A, Battaglio S, Napoli P, Omedè P, Fusaro A, Bruno B, Boccadoro M, Pileri A. Recombinant interferon-gamma inhibits the in vitro proliferation of human myeloma cells. Br J Haematol. 1994 Apr;86(4):726–732. [PubMed]
  • Delvenne P, al-Saleh W, Gilles C, Thiry A, Boniver J. Inhibition of growth of normal and human papillomavirus-transformed keratinocytes in monolayer and organotypic cultures by interferon-gamma and tumor necrosis factor-alpha. Am J Pathol. 1995 Mar;146(3):589–598. [PMC free article] [PubMed]
  • Watanabe Y, Kuribayashi K, Miyatake S, Nishihara K, Nakayama E, Taniyama T, Sakata T. Exogenous expression of mouse interferon gamma cDNA in mouse neuroblastoma C1300 cells results in reduced tumorigenicity by augmented anti-tumor immunity. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9456–9460. [PMC free article] [PubMed]
  • Boehm U, Klamp T, Groot M, Howard JC. Cellular responses to interferon-gamma. Annu Rev Immunol. 1997;15:749–795. [PubMed]
  • Arenberg DA, Kunkel SL, Polverini PJ, Morris SB, Burdick MD, Glass MC, Taub DT, Iannettoni MD, Whyte RI, Strieter RM. Interferon-gamma-inducible protein 10 (IP-10) is an angiostatic factor that inhibits human non-small cell lung cancer (NSCLC) tumorigenesis and spontaneous metastases. J Exp Med. 1996 Sep 1;184(3):981–992. [PMC free article] [PubMed]
  • Bach EA, Aguet M, Schreiber RD. The IFN gamma receptor: a paradigm for cytokine receptor signaling. Annu Rev Immunol. 1997;15:563–591. [PubMed]
  • Rodig S, Kaplan D, Shankaran V, Old L, Schreiber RD. Signaling and signaling dysfunction through the interferon gamma receptor. Eur Cytokine Netw. 1998 Sep;9(3 Suppl):49–53. [PubMed]
  • Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ, Schreiber RD. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7556–7561. [PMC free article] [PubMed]
  • Maier JA, Morelli D, Balsari A. The differential response to interferon gamma by normal and transformed endothelial cells. Biochem Biophys Res Commun. 1995 Sep 14;214(2):582–588. [PubMed]
  • Platanias LC, Fish EN. Signaling pathways activated by interferons. Exp Hematol. 1999 Nov;27(11):1583–1592. [PubMed]
  • Decker T, Kovarik P, Meinke A. GAS elements: a few nucleotides with a major impact on cytokine-induced gene expression. J Interferon Cytokine Res. 1997 Mar;17(3):121–134. [PubMed]
  • Kominsky S, Johnson HM, Bryan G, Tanabe T, Hobeika AC, Subramaniam PS, Torres B. IFNgamma inhibition of cell growth in glioblastomas correlates with increased levels of the cyclin dependent kinase inhibitor p21WAF1/CIP1. Oncogene. 1998 Dec 10;17(23):2973–2979. [PubMed]
  • Harvat BL, Jetten AM. Gamma-interferon induces an irreversible growth arrest in mid-G1 in mammary epithelial cells which correlates with a block in hyperphosphorylation of retinoblastoma. Cell Growth Differ. 1996 Mar;7(3):289–300. [PubMed]
  • Subramaniam PS, Johnson HM. A role for the cyclin-dependent kinase inhibitor p21 in the G1 cell cycle arrest mediated by the type I interferons. J Interferon Cytokine Res. 1997 Jan;17(1):11–15. [PubMed]
  • Ruemmele FM, Gurbindo C, Mansour AM, Marchand R, Levy E, Seidman EG. Effects of interferon gamma on growth, apoptosis, and MHC class II expression of immature rat intestinal crypt (IEC-6) cells. J Cell Physiol. 1998 Jul;176(1):120–126. [PubMed]
  • Vadiveloo PK, Vairo G, Novak U, Royston AK, Whitty G, Filonzi EL, Cragoe EJ, Jr, Hamilton JA. Differential regulation of cell cycle machinery by various antiproliferative agents is linked to macrophage arrest at distinct G1 checkpoints. Oncogene. 1996 Aug 1;13(3):599–608. [PubMed]
  • Tamura T, Ueda S, Yoshida M, Matsuzaki M, Mohri H, Okubo T. Interferon-gamma induces Ice gene expression and enhances cellular susceptibility to apoptosis in the U937 leukemia cell line. Biochem Biophys Res Commun. 1996 Dec 4;229(1):21–26. [PubMed]
  • Arany I, Brysk MM, Calhoun KH, Tyring SK. Differentiation and IFN gamma regulate WAF1/CIP1 transcription in p53-independent and p53-dependent pathways in epithelial cells. In Vivo. 1996 Jan-Feb;10(1):119–123. [PubMed]
  • Xaus J, Cardó M, Valledor AF, Soler C, Lloberas J, Celada A. Interferon gamma induces the expression of p21waf-1 and arrests macrophage cell cycle, preventing induction of apoptosis. Immunity. 1999 Jul;11(1):103–113. [PubMed]
  • Harvat BL, Seth P, Jetten AM. The role of p27Kip1 in gamma interferon-mediated growth arrest of mammary epithelial cells and related defects in mammary carcinoma cells. Oncogene. 1997 May 1;14(17):2111–2122. [PubMed]
  • Matsuoka M, Nishimoto I, Asano S. Interferon-gamma impairs physiologic downregulation of cyclin-dependent kinase inhibitor, p27Kip1, during G1 phase progression in macrophages. Exp Hematol. 1999 Feb;27(2):203–209. [PubMed]
  • Der SD, Yang YL, Weissmann C, Williams BR. A double-stranded RNA-activated protein kinase-dependent pathway mediating stress-induced apoptosis. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3279–3283. [PMC free article] [PubMed]
  • Vairo G, Vadiveloo PK, Royston AK, Rockman SP, Rock CO, Jackowski S, Hamilton JA. Deregulated c-myc expression overrides IFN gamma-induced macrophage growth arrest. Oncogene. 1995 May 18;10(10):1969–1976. [PubMed]
  • Green DR. Apoptotic pathways: the roads to ruin. Cell. 1998 Sep 18;94(6):695–698. [PubMed]
  • Raff M. Cell suicide for beginners. Nature. 1998 Nov 12;396(6707):119–122. [PubMed]
  • Cohen GM. Caspases: the executioners of apoptosis. Biochem J. 1997 Aug 15;326(Pt 1):1–16. [PMC free article] [PubMed]
  • Wolf BB, Green DR. Suicidal tendencies: apoptotic cell death by caspase family proteinases. J Biol Chem. 1999 Jul 16;274(29):20049–20052. [PubMed]
  • Nagata S. Fas-induced apoptosis. Intern Med. 1998 Feb;37(2):179–181. [PubMed]
  • Nagata S. Apoptosis by death factor. Cell. 1997 Feb 7;88(3):355–365. [PubMed]
  • Dighe AS, Richards E, Old LJ, Schreiber RD. Enhanced in vivo growth and resistance to rejection of tumor cells expressing dominant negative IFN gamma receptors. Immunity. 1994 Sep;1(6):447–456. [PubMed]
  • Kano A, Watanabe Y, Takeda N, Aizawa S, Akaike T. Analysis of IFN-gamma-induced cell cycle arrest and cell death in hepatocytes. J Biochem. 1997 Apr;121(4):677–683. [PubMed]
  • Brysk MM, Selvanayagam P, Arany I, Brysk H, Tyring SK, Rajaraman S. Induction of apoptotic nuclei by interferon-gamma and by predesquamin in cultured keratinocytes. J Interferon Cytokine Res. 1995 Dec;15(12):1029–1035. [PubMed]
  • Drexler HG, Zaborski M, Quentmeier H. Interferon-gamma induced proliferation of human myeloid leukaemia cell lines. Br J Haematol. 1997 Sep;98(3):699–710. [PubMed]
  • Perugini RA, McDade TP, Vittimberga FJ, Jr, Callery MP. The molecular and cellular biology of pancreatic cancer. Crit Rev Eukaryot Gene Expr. 1998;8(3-4):377–393. [PubMed]
  • Rosewicz S, Wiedenmann B. Pancreatic carcinoma. Lancet. 1997 Feb 15;349(9050):485–489. [PubMed]
  • Bramhall SR, Allum WH, Jones AG, Allwood A, Cummins C, Neoptolemos JP. Treatment and survival in 13,560 patients with pancreatic cancer, and incidence of the disease, in the West Midlands: an epidemiological study. Br J Surg. 1995 Jan;82(1):111–115. [PubMed]
  • Rosewicz S, Stier U, Brembeck F, Kaiser A, Papadimitriou CA, Berdel WE, Wiedenmann B, Riecken EO. Retinoids: effects on growth, differentiation, and nuclear receptor expression in human pancreatic carcinoma cell lines. Gastroenterology. 1995 Nov;109(5):1646–1660. [PubMed]
  • Yamin TT, Ayala JM, Miller DK. Activation of the native 45-kDa precursor form of interleukin-1-converting enzyme. J Biol Chem. 1996 May 31;271(22):13273–13282. [PubMed]
  • Rozenblum E, Schutte M, Goggins M, Hahn SA, Panzer S, Zahurak M, Goodman SN, Sohn TA, Hruban RH, Yeo CJ, et al. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res. 1997 May 1;57(9):1731–1734. [PubMed]
  • Mäkinen K, Hakala T, Lipponen P, Alhava E, Eskelinen M. Clinical contribution of bcl-2, p53 and Ki-67 proteins in pancreatic ductal adenocarcinoma. Anticancer Res. 1998 Jan-Feb;18(1B):615–618. [PubMed]
  • Hu YX, Watanabe H, Ohtsubo K, Yamaguchi Y, Ha A, Motoo Y, Okai T, Sawabu N. Bcl-2 expression related to altered p53 protein and its impact on the progression of human pancreatic carcinoma. Br J Cancer. 1999 Jun;80(7):1075–1079. [PMC free article] [PubMed]
  • Gansauge F, Gansauge S, Schmidt E, Müller J, Beger HG. Prognostic significance of molecular alterations in human pancreatic carcinoma--an immunohistological study. Langenbecks Arch Surg. 1998 Apr;383(2):152–155. [PubMed]
  • Wada M, Hosotani R, Lee JU, Doi R, Koshiba T, Fujimoto K, Miyamoto Y, Tsuji S, Nakajima S, Okuyama A, et al. An exogenous cdk inhibitor, butyrolactone-I, induces apoptosis with increased Bax/Bcl-2 ratio in p53-mutated pancreatic cancer cells. Anticancer Res. 1998 Jul-Aug;18(4A):2559–2566. [PubMed]
  • Ungefroren H, Voss M, Jansen M, Roeder C, Henne-Bruns D, Kremer B, Kalthoff H. Human pancreatic adenocarcinomas express Fas and Fas ligand yet are resistant to Fas-mediated apoptosis. Cancer Res. 1998 Apr 15;58(8):1741–1749. [PubMed]
  • Phan-Bich L, Buard A, Petit JF, Zeng L, Tenu JP, Chretien P, Monnet I, Boutin C, Bignon J, Lemaire G, et al. Differential responsiveness of human and rat mesothelioma cell lines to recombinant interferon-gamma. Am J Respir Cell Mol Biol. 1997 Feb;16(2):178–186. [PubMed]
  • Burke F, Smith PD, Crompton MR, Upton C, Balkwill FR. Cytotoxic response of ovarian cancer cell lines to IFN-gamma is associated with sustained induction of IRF-1 and p21 mRNA. Br J Cancer. 1999 Jun;80(8):1236–1244. [PMC free article] [PubMed]
  • Buard A, Vivo C, Monnet I, Boutin C, Pilatte Y, Jaurand MC. Human malignant mesothelioma cell growth: activation of janus kinase 2 and signal transducer and activator of transcription 1alpha for inhibition by interferon-gamma. Cancer Res. 1998 Feb 15;58(4):840–847. [PubMed]
  • Bromberg JF, Horvath CM, Wen Z, Schreiber RD, Darnell JE., Jr Transcriptionally active Stat1 is required for the antiproliferative effects of both interferon alpha and interferon gamma. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7673–7678. [PMC free article] [PubMed]
  • Taniguchi T, Lamphier MS, Tanaka N. IRF-1: the transcription factor linking the interferon response and oncogenesis. Biochim Biophys Acta. 1997 Aug 8;1333(1):M9–17. [PubMed]
  • Foon KA, Sherwin SA, Abrams PG, Stevenson HC, Holmes P, Maluish AE, Oldham RK, Herberman RB. A phase I trial of recombinant gamma interferon in patients with cancer. Cancer Immunol Immunother. 1985;20(3):193–197. [PubMed]
  • Hobeika AC, Etienne W, Cruz PE, Subramaniam PS, Johnson HM. IFNgamma induction of p21WAF1 in prostate cancer cells: role in cell cycle, alteration of phenotype and invasive potential. Int J Cancer. 1998 Jul 3;77(1):138–145. [PubMed]
  • Chin YE, Kitagawa M, Su WC, You ZH, Iwamoto Y, Fu XY. Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1. Science. 1996 May 3;272(5262):719–722. [PubMed]
  • Chin YE, Kitagawa M, Kuida K, Flavell RA, Fu XY. Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis. Mol Cell Biol. 1997 Sep;17(9):5328–5337. [PMC free article] [PubMed]
  • Miura M, Zhu H, Rotello R, Hartwieg EA, Yuan J. Induction of apoptosis in fibroblasts by IL-1 beta-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell. 1993 Nov 19;75(4):653–660. [PubMed]
  • Horiuchi M, Yamada H, Akishita M, Ito M, Tamura K, Dzau VJ. Interferon regulatory factors regulate interleukin-1beta-converting enzyme expression and apoptosis in vascular smooth muscle cells. Hypertension. 1999 Jan;33(1):162–166. [PubMed]
  • Kanzaki M, Morris PL. Identification and regulation of testicular interferon-gamma (IFNgamma) receptor subunits: IFNgamma enhances interferon regulatory factor-1 and interleukin-1beta converting enzyme expression. Endocrinology. 1998 May;139(5):2636–2644. [PubMed]
  • Tamura T, Ishihara M, Lamphier MS, Tanaka N, Oishi I, Aizawa S, Matsuyama T, Mak TW, Taki S, Taniguchi T. DNA damage-induced apoptosis and Ice gene induction in mitogenically activated T lymphocytes require IRF-1. Leukemia. 1997 Apr;11 (Suppl 3):439–440. [PubMed]
  • Tamura T, Ishihara M, Lamphier MS, Tanaka N, Oishi I, Aizawa S, Matsuyama T, Mak TW, Taki S, Taniguchi T. An IRF-1-dependent pathway of DNA damage-induced apoptosis in mitogen-activated T lymphocytes. Nature. 1995 Aug 17;376(6541):596–599. [PubMed]
  • Sato T, Selleri C, Young NS, Maciejewski JP. Inhibition of interferon regulatory factor-1 expression results in predominance of cell growth stimulatory effects of interferon-gamma due to phosphorylation of Stat1 and Stat3. Blood. 1997 Dec 15;90(12):4749–4758. [PubMed]
  • Sato T, Selleri C, Young NS, Maciejewski JP. Hematopoietic inhibition by interferon-gamma is partially mediated through interferon regulatory factor-1. Blood. 1995 Nov 1;86(9):3373–3380. [PubMed]
  • Tada S, Saito H, Tsunematsu S, Ebinuma H, Wakabayashi K, Masuda T, Ishii H. Interferon regulatory factor-1 gene abnormality and loss of growth inhibitory effect of interferon-alpha in human hepatoma cell lines. Int J Oncol. 1998 Dec;13(6):1207–1216. [PubMed]
  • Iwase S, Furukawa Y, Kikuchi J, Saito S, Nakamura M, Nakayama R, Horiguchi-Yamada J, Yamada H. Defective binding of IRFs to the initiator element of interleukin-1beta-converting enzyme (ICE) promoter in an interferon-resistant Daudi subline. FEBS Lett. 1999 May 7;450(3):263–267. [PubMed]
  • Wolf BB, Schuler M, Echeverri F, Green DR. Caspase-3 is the primary activator of apoptotic DNA fragmentation via DNA fragmentation factor-45/inhibitor of caspase-activated DNase inactivation. J Biol Chem. 1999 Oct 22;274(43):30651–30656. [PubMed]
  • Simbulan-Rosenthal CM, Rosenthal DS, Iyer S, Boulares H, Smulson ME. Involvement of PARP and poly(ADP-ribosyl)ation in the early stages of apoptosis and DNA replication. Mol Cell Biochem. 1999 Mar;193(1-2):137–148. [PubMed]
  • Kaufmann SH, Desnoyers S, Ottaviano Y, Davidson NE, Poirier GG. Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. Cancer Res. 1993 Sep 1;53(17):3976–3985. [PubMed]
  • An B, Dou QP. Cleavage of retinoblastoma protein during apoptosis: an interleukin 1 beta-converting enzyme-like protease as candidate. Cancer Res. 1996 Feb 1;56(3):438–442. [PubMed]
  • Jänicke RU, Walker PA, Lin XY, Porter AG. Specific cleavage of the retinoblastoma protein by an ICE-like protease in apoptosis. EMBO J. 1996 Dec 16;15(24):6969–6978. [PMC free article] [PubMed]
  • Tan X, Wang JY. The caspase-RB connection in cell death. Trends Cell Biol. 1998 Mar;8(3):116–120. [PubMed]
  • Dou QP, An B. RB and apoptotic cell death. Front Biosci. 1998 Apr 06;3:d419–d430. [PubMed]
  • Berry DE, Lu Y, Schmidt B, Fallon PG, O'Connell C, Hu SX, Xu HJ, Blanck G. Retinoblastoma protein inhibits IFN-gamma induced apoptosis. Oncogene. 1996 Apr 18;12(8):1809–1819. [PubMed]
  • Balachandran S, Kim CN, Yeh WC, Mak TW, Bhalla K, Barber GN. Activation of the dsRNA-dependent protein kinase, PKR, induces apoptosis through FADD-mediated death signaling. EMBO J. 1998 Dec 1;17(23):6888–6902. [PMC free article] [PubMed]
  • Lee SB, Rodríguez D, Rodríguez JR, Esteban M. The apoptosis pathway triggered by the interferon-induced protein kinase PKR requires the third basic domain, initiates upstream of Bcl-2, and involves ICE-like proteases. Virology. 1997 Apr 28;231(1):81–88. [PubMed]
  • Rosewicz S, Weder M, Kaiser A, Riecken EO. Antiproliferative effects of interferon alpha on human pancreatic carcinoma cell lines are associated with differential regulation of protein kinase C isoenzymes. Gut. 1996 Aug;39(2):255–261. [PMC free article] [PubMed]
  • Raveh T, Hovanessian AG, Meurs EF, Sonenberg N, Kimchi A. Double-stranded RNA-dependent protein kinase mediates c-Myc suppression induced by type I interferons. J Biol Chem. 1996 Oct 11;271(41):25479–25484. [PubMed]

Figures and Tables

Figure 1
Pancreatic cancer cells express interferon γ receptor (IFN-γ-R) mRNA transcripts. Total mRNA was extracted, reverse transcribed into cDNA, and amplified using polymerase chain reaction with specific primers directed against the ...
Figure 2
Interferon γ (IFN-γ) activates the Jak-Stat signal transduction pathway in human pancreatic cancer cells. Cells were stimulated with 500 IU/ml IFN-γ for the indicated time periods and Jak-1 (A), Jak-2 (B), and ...
Figure 3
Interferon γ (IFN-γ) stimulation results in transactivation of a GAS driven reporter construct. AsPc-1 cells were transiently transfected with pGL2-GAS and relative luciferase activity was measured after a 24 hour period ...
Figure 4
Interferon γ (IFN-γ) inhibits anchorage dependent and independent growth of human pancreatic cancer cells. Subconfluent cells were treated with 500 IU/ml IFN-γ or vehicle for the indicated time periods (A), or ...
Figure 5
Interferon γ (IFN-γ) treated pancreatic tumour cells contain a subdiploid DNA complement. (A) Time course of representative FACS analyses illustrating the cell cycle distribution of pancreatic cancer cells under control conditions ...
Figure 6
Interferon γ (IFN-γ) induced DNA fragmentation and poly(ADP ribose) polymerase (PARP) cleavage in human pancreatic cancer cell lines. (A) Cells were incubated for four days with 500 IU/ml IFN-γ (lanes 3, 5, 7, and ...
Figure 7
Interferon γ (IFN-γ) treatment regulates retinoblastoma protein (pRb) phosphorylation and abundance in human pancreatic cancer cells. Immunoblot analysis demonstrating the time course of changes in pRb expression and phosphorylation ...
Figure 8
Interferon γ (IFN-γ) mediated apoptosis is prevented by the caspase inhibitor z-vad-fmk. Cells were stimulated for three days with either IFN-γ (500 IU/ml), a combination of IFN-γ and z-vad-fmk at various ...
Figure 9
Interferon γ (IFN-γ) causes upregulation of procaspase-1 and interferon regulatory factor 1 (IRF-1) in pancreatic cancer cell lines. (A) Cells were incubated with vehicle or IFN-γ (500 IU/ml) for the indicated ...

Articles from Gut are provided here courtesy of BMJ Group

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...