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Open Access 01-12-2014 | Research

Synthesis, identification and in vivo studies of tumor-targeting agent peptide doxorubicin (PDOX) to treat peritoneal carcinomatosis of gastric cancer with similar efficacy but reduced toxicity

Authors: Li Tang, Rui Duan, Yan-jun Zhong, Raymond A Firestone, Ya-ping Hong, Ji-guo Li, Yan-chao Xin, Han-lin Wu, Yan Li

Published in: Molecular Cancer | Issue 1/2014

Abstract

Background

This work aimed to synthesize a cathepsin B (CTSB)-cleavable tumor-targeting prodrug peptide doxorubicin (PDOX) and study the in vivo efficacy and toxicities on an animal model of gastric peritoneal carcinomatosis (PC).

Methods

PDOX was synthesized using doxorubicin (DOX) attaching to a CTSB-cleavable dipeptide Ac-Phe-Lys and a para-amino-benzyloxycarbonyl (PABC) spacer. PC model was established by injecting VX2 tumor cells into the gastric sub-mucosa of 40 rabbits, which then were randomized into 4 groups: the Control (n = 10) without treatment, the HIPEC (n = 10) receiving cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC), the PDOX (n = 10) and the DOX (n = 10) receiving systemic chemotherapy with PDOX 50.0 mg/kg or DOX 5.0 mg/kg, respectively, after CRS + HIPEC.

Results

The median overall survivals (OS) were 23.0 d (95% CI: 19.9 d - 26.1 d) in the Control, 41.0 d (36.9 d - 45.1 d) in the HIPEC, 65.0 d (44.1 d - 71.9 d) in the PDOX, and 58.0 d (39.6 d - 54.4 d) in the DOX. Compared with the Control, the OS was extended by 70% in the HIPEC (p < 0.001) and further extended by 40% in the DOX (p = 0.029) and by 58% in the PDOX (p = 0.021), and the PC severity was decreased in the HIPEC and further decreased in the PDOX and DOX. Animals receiving DOX treatment showed hematological toxicities with marked reduction of white blood cells and platelets, as well as cardiac toxicities with significant increases in creatine kinase mb isoenzyme, evident myocardium coagulation necrosis, significant nuclear degeneration, peri-nucleus mitochondria deletion, mitochondria-pyknosis, and abnormal intercalated discs. But these toxicities were not evident in the PDOX.

Conclusions

PDOX is a newly synthesized tumor-targeting prodrug of DOX. Compared with DOX, PDOX has similar efficacy but reduced hematological and cardiac toxicities in treating rabbit model of gastric PC.

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Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Canc J Clin. 2011, 61: 69-90.CrossRef

Yeh JM, Hur C, Schrag D, Kuntz KM, Ezzati M, Stout N, Ward Z, Goldie SJ: Contribution of H. pylori and smoking trends to US incidence of intestinal-type noncardia gastric adenocarcinoma: a microsimulation model. PLoS Med. 2013, 10: e1001451PubMedCentralCrossRefPubMed

Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ: Cancer statistics, 2006. CA Canc J Clin. 2006, 56: 106-130.CrossRef

Peng CW, Wang LW, Zeng WJ, Yang XJ, Li Y: Evaluation of the staging systems for gastric cancer. J Surg Oncol. 2013, 108: 93-105.CrossRefPubMed

Yang XJ, Huang CQ, Suo T, Mei LJ, Yang GL, Chen FL, Zhou YF, Xiong B, Yonemura Y, Li Y: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves survival of patients with peritoneal carcinomatosis from gastric cancer: final results of a phase III randomized clinical trial. Ann Surg Oncol. 2011, 18: 1575-1581.PubMedCentralCrossRefPubMed

Yonemura Y, Elnemr A, Endou Y, Ishibashi H, Mizumoto A, Miura M, Li Y: Surgical results of patients with peritoneal carcinomatosis treated with cytoreductive surgery using a new technique named aqua dissection. Gastroenterol Res Pract. 2012, 2012: 521487PubMedCentralPubMed

Dohchin A, Suzuki J, Seki H, Masutani M, Shiroto H, Kawakami Y: Immunostained cathepsins B and L correlate with depth of invasion and different metastatic pathways in early stage gastric carcinoma. Cancer. 2000, 89: 482-487.CrossRefPubMed

Ebert MP, Krüger S, Fogeron ML, Lamer S, Chen J, Pross M, Schulz HU, Lage H, Heim S, Roessner A, Malfertheiner P, Röcken C: Overexpression of cathepsin B in gastric cancer identified by proteome analysis. Proteomics. 2005, 5: 1693-1704.CrossRefPubMed

Sitabkhan Y, Frankfater A: Differences in the expression of cathepsin B in B16 melanoma metastatic variants depend on transcription factor Sp1. DNA Cell Biol. 2007, 26: 673-682.CrossRefPubMed

10.

Eiján AM, Sandes EO, Riveros MD, Thompson S, Pasik L, Mallagrino H, Celeste F, Casabé AR: High expression of cathepsin B in transitional bladder carcinoma correlates with tumor invasion. Cancer. 2003, 98: 262-268.CrossRefPubMed

11.

Czyzewska J, Guzinska-Ustymowicz K, Kemona A, Bandurski R: The expression of matrix metalloproteinase 9 and cathepsin B in gastric carcinoma is associated with lymph node metastasis, but not with postoperative survival. Folia Histochem Cytobiol. 2008, 46: 57-64.CrossRefPubMed

12.

Sevenich L, Schurigt U, Sachse K, Gajda M, Werner F, Müller S, Vasiljeva O, Schwinde A, Klemm N, Deussing J, Peters C, Reinheckel T: Synergistic antitumor effects of combined cathepsin B and cathepsin Z deficiencies on breast cancer progression and metastasis in mice. Proc Natl Acad Sci USA. 2010, 107: 2497-2502.PubMedCentralCrossRefPubMed

13.

Nouh MA, Mohamed MM, El-Shinawi M, Shaalan MA, Cavallo-Medved D, Khaled HM, Sloane BF: Cathepsin B: Cathepsin B: a potential prognostic marker for inflammatory breast cancer. J Transl Med. 2011, 9: 1PubMedCentralCrossRefPubMed

14.

Atkinson JM, Siller CS, Gill JH: Tumour endoproteases: the cutting edge of cancer drug delivery?. Br J Pharmacol. 2008, 153: 1344-1352.PubMedCentralCrossRefPubMed

15.

Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ: MAGIC trial participants: perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006, 355: 11-20.CrossRefPubMed

16.

Dubowchik GM, Firestone RA: Cathepsin B -sensitive dipeptide prodrugs. 1. A model study of structural requirements for efficient release of doxorubicin. Bioorg Med Chem Lett. 1998, 8: 3341-3346.CrossRefPubMed

17.

Dubowchik GM, Mosure K, Knipe JO, Firestone RA: Cathepsin B -sensitive dipeptide prodrugs. 2. Models of anticancer drugs paclitaxel (Taxol), mitomycin C and doxorubicin. Bioorg Med Chem Lett. 1998, 8: 3347-3352.CrossRefPubMed

18.

Dubowchik GM, Firestone RA, Padilla L, Willner D, Hofstead SJ, Mosure K, Knipe JO, Lasch SJ, Trail PA: Cathepsin B -labile dipeptide linkers for lysosomal release of doxorubicin from internalizing immunoconjugates: model studies of enzymatic drug release and antigen-specific in vitro anticancer activity. Bioconjug Chem. 2002, 13: 855-869.CrossRefPubMed

19.

Gocheva V, Joyce JA: Cysteine cathepsins and the cutting edge of cancer invasion. Cell Cycle. 2007, 6: 60-64.CrossRefPubMed

20.

Vasiljeva O, Papazoglou A, Krüger A, Brodoefel H, Korovin M, Deussing J, Augustin N, Nielsen BS, Almholt K, Bogyo M, Peters C, Reinheckel T: Tumor cell-derived and macrophage-derived cathepsin B promotes progression and lung metastasis of mammary cancer. Cancer Res. 2006, 66: 5242-5250.CrossRefPubMed

21.

Azoulay M, Florent JC, Monneret C, Gesson JP, Jacquesy JC, Tillequin F, Koch M, Bosslet K, Czech J, Hoffman D: Prodrugs of anthracycline antibiotics suited for tumor-specific activation. Anticancer Drug Des. 1995, 10: 441-450.PubMed

22.

Sadeghi B, Arvieux C, Glehen O, Beaujard AC, Rivoire M, Baulieux J, Fontaumard E, Brachet A, Caillot JL, Faure JL, Porcheron J, Peix JL, Francois Y, Vignal J, Gilly FN: Peritoneal carcinomatosis from nongynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer. 2000, 88: 358-363.CrossRefPubMed

23.

Fujimoto S, Shrestha RD, Kokubun M, Ohta M, Takahashi M, Kobayashi K, Kiuchi S, Okui K, Miyoshi T, Arimizu N: Intraperitoneal hyperthermic perfusion combined with surgery effective for gastric cancer patients with peritoneal seeding. Ann Surg. 1988, 208: 36-41.PubMedCentralCrossRefPubMed

24.

Mei LJ, Yang XJ, Tang L, Al-shammaa HAH, Yonemura Y, Li Y: Establishment and identification of a rabbit model of peritoneal carcinomatosis from gastric cancer. BMC Canc. 2010, 10: 124CrossRef

25.

Tang L, Mei LJ, Yang XJ, Huang CQ, Zhou YF, Yonemura Y, Li Y: Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy improves survival of gastric cancer with peritoneal carcinomatosis: evidence from an experimental study. J Transl Med. 2011, 9: 53PubMedCentralCrossRefPubMed

26.

Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA: Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med. 2001, 345: 725-730.CrossRefPubMed

27.

Chua YJ, Cunningham D: The UK NCRI MAGIC trial of perioperative chemotherapy in resectable gastric cancer: implications for clinical practice. Ann Surg Oncol. 2007, 14: 2687-2690.CrossRefPubMed

28.

D'Ugo D, Rausei S, Biondi A, Persiani R: Preoperative treatment and surgery in gastric cancer: friends or foes?. Lancet Oncol. 2009, 10: 191-195.CrossRefPubMed

29.

Rabbani A, Finn RM, Ausio J: The anthracycline antibiotics: antitumor drugs that alter chromatin structure. Bioessays. 2005, 27: 50-56.CrossRefPubMed

30.

Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Rüschoff J, Kang YK, : Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010, 376: 687-697.CrossRefPubMed

31.

Stylianopoulos T, Jain RK: Combining two strategies to improve perfusion and drug delivery in solid tumors. Proc Natl Acad Sci USA. 2013, 110: 18632-18637.PubMedCentralCrossRefPubMed

32.

Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, Stylianopoulos T, Mousa AS, Han X, Adstamongkonkul P, Popović Z, Huang P, Bawendi MG, Boucher Y, Jain RK: Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun. 2013, 4: 2516PubMedCentralCrossRefPubMed

33.

Chauhan VP, Stylianopoulos T, Boucher Y, Jain RK: Delivery of molecular and nanoscale medicine to tumors: transport barriers and strategies. Annu Rev Chem Biomol Eng. 2011, 2: 281-298.CrossRefPubMed

34.

Gong F, Peng X, Luo C, Shen G, Zhao C, Zou L, Li L, Sang Y, Zhao Y, Zhao X: Cathepsin B as a potential prognostic and therapeutic marker for human lung squamous cell carcinoma. Mol Canc. 2013, 12: 125CrossRef

35.

Nomura T, Katunuma N: Involvement of cathepsins in the invasion, metastasis and proliferation of cancer cells. J Med Invest. 2005, 52: 1-9.CrossRefPubMed

36.

Swenson CE, Perkins WR, Roberts P, Janoff AS: Liposome technology and the development of Myocet(TM) (liposomal doxorubicin citrate). Breast. 2001, 10: 1-7.CrossRef

37.

Batist G1, Ramakrishnan G, Rao CS, Chandrasekharan A, Gutheil J, Guthrie T, Shah P, Khojasteh A, Nair MK, Hoelzer K, Tkaczuk K, Park YC, Lee LW: Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J Clin Oncol. 2001, 19: 1444-1454.PubMed

38.

Harris L, Batist G, Belt R, Rovira D, Navari R, Azarnia N, Welles L, Winer E, : Liposome encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer. 2002, 94: 25-36.CrossRefPubMed

39.

Lai R, Long Y, Li Q, Zhang X, Rong T: Oxidative stress markers may not be early markers of doxorubicin-induced cardiotoxicity in rabbits. Exp Ther Med. 2011, 2: 947-950.PubMedCentralPubMed

40.

Zhang S, Liu X, Bawa-Khalfe T, Lu LS, Lyu YL, Liu LF, Yeh ET: Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med. 2012, 18: 1639-1642.CrossRefPubMed

41.

Viswanatha Swamy AHM, Wangikar U, Koti BC, Thippeswamy AHM, Ronad PM, Manjula DV: Cardioprotective effect of ascorbic acid on doxorubicin-induced myocardial toxicity in rats. Indian J Pharmacol. 2011, 43: 507-511.PubMedCentralCrossRefPubMed

42.

Rahman A, Alam M, Rao S, Cai L, Clark LT, Shafiq S, Siddiqui MA: Differential effects of doxorubicin on atrial natriuretic peptide expression in vivo and in vitro. Biol Res. 2001, 34: 195-206.CrossRefPubMed

43.

Kidd JG, Rous P: A transplantable rabbit carcinoma originating in a virusinduced papilloma and containing the virus in masked or altered form. J Exp Med. 1940, 71: 813-838.PubMedCentralCrossRefPubMed

44.

Monneuse O, Mestrallet JP, Quash G, Gilly FN, Glehen O: Intraperitoneal treatment with dimethylthioampal (DIMATE) combined with surgical debulking is effective for experimental peritoneal carcinomatosis in a rat model. J Gastrointest Surg. 2005, 9: 769-774.CrossRefPubMed

Title: Synthesis, identification and in vivo studies of tumor-targeting agent peptide doxorubicin (PDOX) to treat peritoneal carcinomatosis of gastric cancer with similar efficacy but reduced toxicity
Authors: Li Tang
Rui Duan
Yan-jun Zhong
Raymond A Firestone
Ya-ping Hong
Ji-guo Li
Yan-chao Xin
Han-lin Wu
Yan Li
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: Molecular Cancer / Issue 1/2014
Electronic ISSN: 1476-4598
DOI: https://doi.org/10.1186/1476-4598-13-44

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