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Plitidepsin

Plitidepsin is a cyclic depsipeptide isolated from the marine tunicate Aplidium albicans. Plitidepsin displays a broad spectrum of antitumor activities, inducing apoptosis by triggering mitochondrial cytochrome c release, initiating the Fas/DC95, JNK pathway and activating caspase 3 activation. This agent also inhibits elongation factor 1-a, thereby interfering with protein synthesis, and induces G1 arrest and G2 blockade, thereby inhibiting tumor cell growth. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

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 1: Rockwell S, Liu Y. Aplidin as a potential adjunct to radiation therapy: in vitro studies. Int J Radiat Biol. 2010 Jan;86(1):63-70. PubMed PMID: 20070217; PubMed Central PMCID: PMC2837581.

2: Longo-Sorbello GS, Gao H, Mishra PJ, Kamen B, Soto A, Jimeno J, Aracil M, Paz de Paz MF, Bertino JR, Banerjee D. Heparin and suramin alter plitidepsin uptake via inhibition of GPCR coupled signaling. J Chemother. 2009 Nov;21(5):550-7. PubMed PMID: 19933047.

3: Dumez H, Gallardo E, Culine S, Galceran JC, Schöffski P, Droz JP, Extremera S, Szyldergemajn S, Fléchon A. Phase II study of biweekly plitidepsin as second-line therapy for advanced or metastatic transitional cell carcinoma of the urothelium. Mar Drugs. 2009 Sep 16;7(3):451-63. PubMed PMID: 19841725; PubMed Central PMCID: PMC2763111.

4: Baudin E, Droz JP, Paz-Ares L, van Oosterom AT, Cullell-Young M, Schlumberger M. Phase II study of plitidepsin 3-hour infusion every 2 weeks in patients with unresectable advanced medullary thyroid carcinoma. Am J Clin Oncol. 2010 Feb;33(1):83-8. PubMed PMID: 19704366.

5: Le Tourneau C, Faivre S, Ciruelos E, Domínguez MJ, López-Martín JA, Izquierdo MA, Jimeno J, Raymond E. Reports of clinical benefit of plitidepsin (Aplidine), a new marine-derived anticancer agent, in patients with advanced medullary thyroid carcinoma. Am J Clin Oncol. 2010 Apr;33(2):132-6. PubMed PMID: 19687728.

6: Muñoz-Alonso MJ, González-Santiago L, Martínez T, Losada A, Galmarini CM, Muñoz A. The mechanism of action of plitidepsin. Curr Opin Investig Drugs. 2009 Jun;10(6):536-42. Review. PubMed PMID: 19513942.

7: Eisen T, Thomas J, Miller WH Jr, Gore M, Wolter P, Kavan P, Martín JA, Lardelli P. Phase II study of biweekly plitidepsin as second-line therapy in patients with advanced malignant melanoma. Melanoma Res. 2009 Jun;19(3):185-92. PubMed PMID: 19436178.

8: Morton CL, Houghton PJ, Gorlick R, Kolb EA, Lock R, Carol H, Keir ST, Reynolds CP, Kang MH, Maris JM, Billups C, Smith MA. Initial testing of aplidin by the pediatric pre-clinical testing program. Pediatr Blood Cancer. 2009 Sep;53(3):509-12. PubMed PMID: 19418543; PubMed Central PMCID: PMC2777698.

9: Schöffski P, Guillem V, Garcia M, Rivera F, Tabernero J, Cullell M, Lopez-Martin JA, Pollard P, Dumez H, del Muro XG, Paz-Ares L. Phase II randomized study of Plitidepsin (Aplidin), alone or in association with L-carnitine, in patients with unresectable advanced renal cell carcinoma. Mar Drugs. 2009;7(1):57-70. Epub 2009 Mar 5. PubMed PMID: 19370171; PubMed Central PMCID: PMC2666889.

10: Ocio EM, Mateos MV, Maiso P, Pandiella A, San-Miguel JF. New drugs in multiple myeloma: mechanisms of action and phase I/II clinical findings. Lancet Oncol. 2008 Dec;9(12):1157-65. Review. PubMed PMID: 19038762.

11: Nalda-Molina R, Valenzuela B, Ramon-Lopez A, Miguel-Lillo B, Soto-Matos A, Perez-Ruixo JJ. Population pharmacokinetics meta-analysis of plitidepsin (Aplidin) in cancer subjects. Cancer Chemother Pharmacol. 2009 Jun;64(1):97-108. Epub 2008 Oct 22. PubMed PMID: 18941750.

12: Eisen T, Thatcher N, Leyvraz S, Miller WH Jr, Couture F, Lorigan P, Lüthi F, Small D, Tanovic A, O'Brien M. Phase II study of weekly plitidepsin as second-line therapy for small cell lung cancer. Lung Cancer. 2009 Apr;64(1):60-5. Epub 2008 Aug 9. PubMed PMID: 18692272.

13: Singh R, Sharma M, Joshi P, Rawat DS. Clinical status of anti-cancer agents derived from marine sources. Anticancer Agents Med Chem. 2008 Aug;8(6):603-17. Review. PubMed PMID: 18690825.

14: Mitsiades CS, Ocio EM, Pandiella A, Maiso P, Gajate C, Garayoa M, Vilanova D, Montero JC, Mitsiades N, McMullan CJ, Munshi NC, Hideshima T, Chauhan D, Aviles P, Otero G, Faircloth G, Mateos MV, Richardson PG, Mollinedo F, San-Miguel JF, Anderson KC. Aplidin, a marine organism-derived compound with potent antimyeloma activity in vitro and in vivo. Cancer Res. 2008 Jul 1;68(13):5216-25. PubMed PMID: 18593922.

15: Caers J, Menu E, De Raeve H, Lepage D, Van Valckenborgh E, Van Camp B, Alvarez E, Vanderkerken K. Antitumour and antiangiogenic effects of Aplidin in the 5TMM syngeneic models of multiple myeloma. Br J Cancer. 2008 Jun 17;98(12):1966-74. Epub 2008 Jun 3. PubMed PMID: 18521088; PubMed Central PMCID: PMC2441967.

16: Izquierdo MA, Bowman A, García M, Jodrell D, Martinez M, Pardo B, Gómez J, López-Martin JA, Jimeno J, Germá JR, Smyth JF. Phase I clinical and pharmacokinetic study of plitidepsin as a 1-hour weekly intravenous infusion in patients with advanced solid tumors. Clin Cancer Res. 2008 May 15;14(10):3105-12. PubMed PMID: 18483378.

17: Russo GL, Ciarcia G, Presidente E, Siciliano RA, Tosti E. Cytotoxic and apoptogenic activity of a methanolic extract from the marine invertebrate Ciona intestinalis on malignant cell lines. Med Chem. 2008 Mar;4(2):106-9. PubMed PMID: 18336328.

18: Muñoz-Alonso MJ, González-Santiago L, Zarich N, Martínez T, Alvarez E, Rojas JM, Muñoz A. Plitidepsin has a dual effect inhibiting cell cycle and inducing apoptosis via Rac1/c-Jun NH2-terminal kinase activation in human melanoma cells. J Pharmacol Exp Ther. 2008 Mar;324(3):1093-101. Epub 2007 Dec 18. PubMed PMID: 18089842.

19: Peschel C, Hartmann JT, Schmittel A, Bokemeyer C, Schneller F, Keilholz U, Buchheidt D, Millan S, Izquierdo MA, Hofheinz RD. Phase II study of plitidepsin in pretreated patients with locally advanced or metastatic non-small cell lung cancer. Lung Cancer. 2008 Jun;60(3):374-80. Epub 2007 Dec 3. PubMed PMID: 18054408.

20: Le Tourneau C, Raymond E, Faivre S. Aplidine: a paradigm of how to handle the activity and toxicity of a novel marine anticancer poison. Curr Pharm Des. 2007;13(33):3427-39. Review. PubMed PMID: 18045196.

21: Adrian TE. Novel marine-derived anti-cancer agents. Curr Pharm Des. 2007;13(33):3417-26. Review. PubMed PMID: 18045195.

22: Humeniuk R, Menon LG, Mishra PJ, Saydam G, Longo-Sorbello GS, Elisseyeff Y, Lewis LD, Aracil M, Jimeno J, Bertino JR, Banerjee D. Aplidin synergizes with cytosine arabinoside: functional relevance of mitochondria in Aplidin-induced cytotoxicity. Leukemia. 2007 Dec;21(12):2399-405. Epub 2007 Aug 23. PubMed PMID: 17713546.

23: Moneo V, Serelde BG, Leal JF, Blanco-Aparicio C, Diaz-Uriarte R, Aracil M, Tercero JC, Jimeno J, Carnero A. Levels of p27(kip1) determine Aplidin sensitivity. Mol Cancer Ther. 2007 Apr;6(4):1310-6. PubMed PMID: 17431109.

24: González-Santiago L, Alfonso P, Suárez Y, Núñez A, García-Fernández LF, Alvarez E, Muñoz A, Casal JI. Proteomic analysis of the resistance to aplidin in human cancer cells. J Proteome Res. 2007 Apr;6(4):1286-94. Epub 2007 Mar 6. PubMed PMID: 17338558.

25: Blackhall FH, Shepherd FA. Small cell lung cancer and targeted therapies. Curr Opin Oncol. 2007 Mar;19(2):103-8. Review. PubMed PMID: 17272981.

26: Maroun JA, Belanger K, Seymour L, Matthews S, Roach J, Dionne J, Soulieres D, Stewart D, Goel R, Charpentier D, Goss G, Tomiak E, Yau J, Jimeno J, Chiritescu G; National Cancer Institute of Canada Clinical Trials Group. Phase I study of Aplidine in a dailyx5 one-hour infusion every 3 weeks in patients with solid tumors refractory to standard therapy. A National Cancer Institute of Canada Clinical Trials Group study: NCIC CTG IND 115. Ann Oncol. 2006 Sep;17(9):1371-8. PubMed PMID: 16966366.

27: Faivre S, Raymond E. Management of neuromuscular dose limiting toxicity at the early stage of drug development. Ann Oncol. 2006 Sep;17(9):1343-6. PubMed PMID: 16966365.

28: Suárez Y, González-Santiago L, Zarich N, Dávalos A, Aranda JF, Alonso MA, Lasunción MA, Rojas JM, Muñoz A. Plitidepsin cellular binding and Rac1/JNK pathway activation depend on membrane cholesterol content. Mol Pharmacol. 2006 Nov;70(5):1654-63. Epub 2006 Aug 23. PubMed PMID: 16928956.

29: O'Hanlon LH. Scientists are searching the seas for cancer drugs. J Natl Cancer Inst. 2006 May 17;98(10):662-3. PubMed PMID: 16705115.

30: Brandon EF, Sparidans RW, van Ooijen RD, Meijerman I, Lazaro LL, Manzanares I, Beijnen JH, Schellens JH. In vitro characterization of the human biotransformation pathways of aplidine, a novel marine anti-cancer drug. Invest New Drugs. 2007 Feb;25(1):9-19. PubMed PMID: 16633717.

31: González-Santiago L, Suárez Y, Zarich N, Muñoz-Alonso MJ, Cuadrado A, Martínez T, Goya L, Iradi A, Sáez-Tormo G, Maier JV, Moorthy A, Cato AC, Rojas JM, Muñoz A. Aplidin induces JNK-dependent apoptosis in human breast cancer cells via alteration of glutathione homeostasis, Rac1 GTPase activation, and MKP-1 phosphatase downregulation. Cell Death Differ. 2006 Nov;13(11):1968-81. Epub 2006 Mar 17. PubMed PMID: 16543941.

32: Rawat DS, Joshi MC, Joshi P, Atheaya H. Marine peptides and related compounds in clinical trial. Anticancer Agents Med Chem. 2006 Jan;6(1):33-40. Review. PubMed PMID: 16475925.

33: Adrio J, Cuevas C, Manzanares I, Joullié MM. Synthesis and biological evaluation of tamandarin B analogues. Org Lett. 2006 Feb 2;8(3):511-4. PubMed PMID: 16435872.

34: Taddei ML, Chiarugi P, Cuevas C, Ramponi G, Raugei G. Oxidation and inactivation of low molecular weight protein tyrosine phosphatase by the anticancer drug Aplidin. Int J Cancer. 2006 Apr 15;118(8):2082-8. PubMed PMID: 16287083.

35: Bravo SB, García-Rendueles ME, Seoane R, Dosil V, Cameselle-Teijeiro J, López-Lázaro L, Zalvide J, Barreiro F, Pombo CM, Alvarez CV. Plitidepsin has a cytostatic effect in human undifferentiated (anaplastic) thyroid carcinoma. Clin Cancer Res. 2005 Nov 1;11(21):7664-73. PubMed PMID: 16278386.

36: Tognon G, Bernasconi S, Celli N, Faircloth GT, Cuevas C, Jimeno J, Erba E, D'Incalci M. Induction of resistance to Aplidin in a human ovarian cancer cell line related to MDR expression. Cancer Biol Ther. 2005 Dec;4(12):1325-30. Epub 2005 Dec 8. PubMed PMID: 16258264.

37: Calvert AH. Fishing for new drugs. J Clin Oncol. 2005 Nov 1;23(31):7780-2. Epub 2005 Oct 3. PubMed PMID: 16204006.

38: Faivre S, Chièze S, Delbaldo C, Ady-Vago N, Guzman C, Lopez-Lazaro L, Lozahic S, Jimeno J, Pico F, Armand JP, Martin JA, Raymond E. Phase I and pharmacokinetic study of aplidine, a new marine cyclodepsipeptide in patients with advanced malignancies. J Clin Oncol. 2005 Nov 1;23(31):7871-80. Epub 2005 Sep 19. PubMed PMID: 16172454.

39: Biscardi M, Caporale R, Balestri F, Gavazzi S, Jimeno J, Grossi A. VEGF inhibition and cytotoxic effect of aplidin in leukemia cell lines and cells from acute myeloid leukemia. Ann Oncol. 2005 Oct;16(10):1667-74. Epub 2005 Jul 13. PubMed PMID: 16014640.

40: Straight AM, Oakley K, Moores R, Bauer AJ, Patel A, Tuttle RM, Jimeno J, Francis GL. Aplidin reduces growth of anaplastic thyroid cancer xenografts and the expression of several angiogenic genes. Cancer Chemother Pharmacol. 2006 Jan;57(1):7-14. Epub 2005 Nov 5. PubMed PMID: 16001179.

41: Brandon EF, van Ooijen RD, Sparidans RW, Lázaro LL, Heck AJ, Beijnen JH, Schellens JH. Structure elucidation of aplidine metabolites formed in vitro by human liver microsomes using triple quadrupole mass spectrometry. J Mass Spectrom. 2005 Jun;40(6):821-31. PubMed PMID: 15892174.

42: D'Incalci M, Simone M, Tavecchio M, Damia G, Garbi A, Erba E. New drugs from the sea. J Chemother. 2004 Nov;16 Suppl 4:86-9. Review. PubMed PMID: 15688619.

43: Gajate C, Mollinedo F. Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy. J Biol Chem. 2005 Mar 25;280(12):11641-7. Epub 2005 Jan 19. PubMed PMID: 15659383.

44: Gutiérrez-Rodríguez M, Martín-Martínez M, García-López MT, Herranz R, Cuevas F, Polanco C, Rodríguez-Campos I, Manzanares I, Cárdenas F, Feliz M, Lloyd-Williams P, Giralt E. Synthesis, conformational analysis, and cytotoxicity of conformationally constrained aplidine and tamandarin A analogues incorporating a spirolactam beta-turn mimetic. J Med Chem. 2004 Nov 4;47(23):5700-12. PubMed PMID: 15509169.

45: Losada A, López-Oliva JM, Sánchez-Puelles JM, García-Fernández LF. Establishment and characterisation of a human carcinoma cell line with acquired resistance to Aplidin. Br J Cancer. 2004 Oct 4;91(7):1405-13. PubMed PMID: 15365569; PubMed Central PMCID: PMC2409906.

46: Taraboletti G, Poli M, Dossi R, Manenti L, Borsotti P, Faircloth GT, Broggini M, D'Incalci M, Ribatti D, Giavazzi R. Antiangiogenic activity of aplidine, a new agent of marine origin. Br J Cancer. 2004 Jun 14;90(12):2418-24. PubMed PMID: 15173857; PubMed Central PMCID: PMC2409535.

47: Celli N, Mariani B, Di Carlo F, Zucchetti M, Lopez-Lazaro L, D'Incalci M, Rotilio D. Determination of aplidin, a marine-derived anticancer drug, in human plasma, whole blood and urine by liquid chromatography with electrospray ionisation tandem mass spectrometric detection. J Pharm Biomed Anal. 2004 Feb 18;34(3):619-30. PubMed PMID: 15127818.

48: Cuadrado A, González L, Suárez Y, Martínez T, Muñoz A. JNK activation is critical for Aplidin-induced apoptosis. Oncogene. 2004 Jun 10;23(27):4673-80. PubMed PMID: 15122339.

49: Jimeno J, López-Martín JA, Ruiz-Casado A, Izquierdo MA, Scheuer PJ, Rinehart K. Progress in the clinical development of new marine-derived anticancer compounds. Anticancer Drugs. 2004 Apr;15(4):321-9. Review. PubMed PMID: 15057135.

50: Sparidans RW, Schellens JH, López-Lázaro L, Jimeno JM, Beijnen JH. Liquid chromatographic assay for the cyclic depsipeptide aplidine, a new marine antitumor drug, in whole blood using derivatization with trans-4'-hydrazino-2-stilbazole. Biomed Chromatogr. 2004 Jan;18(1):16-20. PubMed PMID: 14872544.

51: Cárdenas F, Caba JM, Feliz M, Lloyd-Williams P, Giralt E. Analysis of conformational equilibria in aplidine using selective excitation 2D NMR spectroscopy and molecular mechanics/dynamics calculations. J Org Chem. 2003 Dec 12;68(25):9554-62. PubMed PMID: 14656079.

52: Gómez SG, Bueren JA, Faircloth GT, Jimeno J, Albella B. In vitro toxicity of three new antitumoral drugs (trabectedin, aplidin, and kahalalide F) on hematopoietic progenitors and stem cells. Exp Hematol. 2003 Nov;31(11):1104-11. PubMed PMID: 14585376.

53: Pérez M, Sadqi M, Muñoz V, Avila J. Inhibition by Aplidine of the aggregation of the prion peptide PrP 106-126 into beta-sheet fibrils. Biochim Biophys Acta. 2003 Oct 15;1639(2):133-9. PubMed PMID: 14559120.

54: Erba E, Serafini M, Gaipa G, Tognon G, Marchini S, Celli N, Rotilio D, Broggini M, Jimeno J, Faircloth GT, Biondi A, D'Incalci M. Effect of Aplidin in acute lymphoblastic leukaemia cells. Br J Cancer. 2003 Aug 18;89(4):763-73. PubMed PMID: 12915891; PubMed Central PMCID: PMC2376915.

55: Schwartsmann G, Da Rocha AB, Mattei J, Lopes R. Marine-derived anticancer agents in clinical trials. Expert Opin Investig Drugs. 2003 Aug;12(8):1367-83. PubMed PMID: 12882622.

56: Yin J, Aviles P, Lee W, Ly C, Floriano P, Ignacio M, Faircloth G. Development of a liquid chromatography/tandem mass spectrometry assay for the quantification of Aplidin, a novel marine-derived antineoplastic agent, in human plasma. Rapid Commun Mass Spectrom. 2003;17(16):1909-14. PubMed PMID: 12876692.

57: Bresters D, Broekhuizen AJ, Kaaijk P, Faircloth GT, Jimeno J, Kaspers GJ. In vitro cytotoxicity of aplidin and crossresistance with other cytotoxic drugs in childhood leukemic and normal bone marrow and blood samples: a rational basis for clinical development. Leukemia. 2003 Jul;17(7):1338-43. PubMed PMID: 12835722.

58: Taguchi T. [Development of marine-derived anti-cancer compounds]. Gan To Kagaku Ryoho. 2003 May;30(5):579-88. Review. Japanese. PubMed PMID: 12795086.

59: Yao L. Aplidin PharmaMar. IDrugs. 2003 Mar;6(3):246-50. Review. PubMed PMID: 12789614.

60: Donia M, Hamann MT. Marine natural products and their potential applications as anti-infective agents. Lancet Infect Dis. 2003 Jun;3(6):338-48. Review. PubMed PMID: 12781505.

61: Bayés M, Rabasseda X, Prous JR. Gateways to clinical trials. March 2003. Methods Find Exp Clin Pharmacol. 2003 Mar;25(2):145-68. PubMed PMID: 12731460.

62: Aplidin increases sensitivity to treatment in leukemia and lymphoma cells. Expert Rev Anticancer Ther. 2003 Apr;3(2):133-4. PubMed PMID: 12722872.

63: Gajate C, An F, Mollinedo F. Rapid and selective apoptosis in human leukemic cells induced by Aplidine through a Fas/CD95- and mitochondrial-mediated mechanism. Clin Cancer Res. 2003 Apr;9(4):1535-45. PubMed PMID: 12684430.

64: Broggini M, Marchini SV, Galliera E, Borsotti P, Taraboletti G, Erba E, Sironi M, Jimeno J, Faircloth GT, Giavazzi R, D'Incalci M. Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT-4. Leukemia. 2003 Jan;17(1):52-9. PubMed PMID: 12529660.

65: Marchini S, Chiorino G, Faircloth GT, D'Incalci M. Changes in gene expression profile induced by the anticancer agent Aplidine in Molt-4 leukemic cell lines. J Biol Regul Homeost Agents. 2002 Jul-Sep;16(3):241-8. PubMed PMID: 12456028.

66: Cuadrado A, Garcia-Fernandez LF, Gonzalez L, Suarez Y, Losada A, Alcaide V, Martinez T, Fernandez-Sousa JM, Sanchez-Puelles JM, Munoz A. Aplidin induces apoptosis in human cancer cells via glutathione depletion and sustained activation of the epidermal growth factor receptor, Src, JNK, and p38 MAPK. J Biol Chem. 2003 Jan 3;278(1):241-50. Epub 2002 Oct 31. PubMed PMID: 12414812.

67: García-Fernández LF, Losada A, Alcaide V, Alvarez AM, Cuadrado A, González L, Nakayama K, Nakayama KI, Fernández-Sousa JM, Muñoz A, Sánchez-Puelles JM. Aplidin induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C delta. Oncogene. 2002 Oct 24;21(49):7533-44. PubMed PMID: 12386816.

68: Jimeno JM. A clinical armamentarium of marine-derived anti-cancer compounds. Anticancer Drugs. 2002 May;13 Suppl 1:S15-9. Review. PubMed PMID: 12173490.

69: Albella B, Faircloth G, López-Lázaro L, Guzmán C, Jimeno J, Bueren JA. In vitro toxicity of ET-743 and aplidine, two marine-derived antineoplastics, on human bone marrow haematopoietic progenitors. comparison with the clinical results. Eur J Cancer. 2002 Jul;38(10):1395-404. PubMed PMID: 12091072.

70: D'Incalci M. Editorial comment on "In vitro toxicity of ET-743 and Aplidine, two marine-derived antineoplastics, on human bone marrow haematopoietic progenitors: comparison with the clinical results" by Albella and colleagues. Eur J Cancer. 2002 Jul;38(10):1297. PubMed PMID: 12091058.

71: Erba E, Bassano L, Di Liberti G, Muradore I, Chiorino G, Ubezio P, Vignati S, Codegoni A, Desiderio MA, Faircloth G, Jimeno J, D'Incalci M. Cell cycle phase perturbations and apoptosis in tumour cells induced by aplidine. Br J Cancer. 2002 May 6;86(9):1510-7. PubMed PMID: 11986788; PubMed Central PMCID: PMC2375382.

72: Schwartsmann G, Brondani da Rocha A, Berlinck RG, Jimeno J. Marine organisms as a source of new anticancer agents. Lancet Oncol. 2001 Apr;2(4):221-5. Review. PubMed PMID: 11905767.

73: Vera MD, Joullié MM. Natural products as probes of cell biology: 20 years of didemnin research. Med Res Rev. 2002 Mar;22(2):102-45. Review. PubMed PMID: 11857636.

74: da Rocha AB, Lopes RM, Schwartsmann G. Natural products in anticancer therapy. Curr Opin Pharmacol. 2001 Aug;1(4):364-9. Review. PubMed PMID: 11710734.

75: Gómez SG, Faircloth G, López-Lázaro L, Jimeno J, Bueren JA, Albella B. In vitro hematotoxicity of Aplidine on human bone marrow and cord blood progenitor cells. Toxicol In Vitro. 2001 Aug-Oct;15(4-5):347-50. PubMed PMID: 11566561.

76: Cárdenas F, Thormann M, Feliz M, Caba JM, Lloyd-Williams P, Giralt E. Conformational analysis of dehydrodidemnin B (aplidine) by NMR spectroscopy and molecular mechanics/dynamics calculations. J Org Chem. 2001 Jun 29;66(13):4580-4. PubMed PMID: 11421777.

77: Waterval JC, Bloks JC, Sparidans RW, Beijnen JH, Rodriguez-Campos IM, Bult A, Lingeman H, Underberg WJ. Degradation kinetics of aplidine, a new marine antitumoural cyclic peptide, in aqueous solution. J Chromatogr B Biomed Sci Appl. 2001 Apr 15;754(1):161-8. PubMed PMID: 11318411.

78: Mastbergen SC, Duivenvoorden I, Versteegh RT, Geldof AA. Cell cycle arrest and clonogenic tumor cell kill by divergent chemotherapeutic drugs. Anticancer Res. 2000 May-Jun;20(3A):1833-8. PubMed PMID: 10928115.

79: Nuijen B, Bouma M, Henrar RE, Floriano P, Jimeno JM, Talsma H, Kettenes-van den Bosch JJ, Heck AJ, Bult A, Beijnen JH. Pharmaceutical development of a parenteral lyophilized formulation of the novel antitumor agent aplidine. PDA J Pharm Sci Technol. 2000 May-Jun;54(3):193-208. PubMed PMID: 10927911.

80: Nuijen B, Bouma M, Henrar RE, Manada C, Bult A, Beijnen JH. Compatibility and stability of aplidine, a novel marine-derived depsipeptide antitumor agent, in infusion devices, and its hemolytic and precipitation potential upon i.v. administration. Anticancer Drugs. 1999 Nov;10(10):879-87. PubMed PMID: 10630355.

81: Rinehart KL. Antitumor compounds from tunicates. Med Res Rev. 2000 Jan;20(1):1-27. Review. PubMed PMID: 10608919.

82: Celli N, Gallardo AM, Rossi C, Zucchetti M, D'Incalci M, Rotilio D. Analysis of aplidine (dehydrodidemnin B), a new marine-derived depsipeptide, in rat biological fluids by liquid chromatography-tandem mass spectrometry. J Chromatogr B Biomed Sci Appl. 1999 Aug 20;731(2):335-43. PubMed PMID: 10510788.

83: Geldof AA, Mastbergen SC, Henrar RE, Faircloth GT. Cytotoxicity and neurocytotoxicity of new marine anticancer agents evaluated using in vitro assays. Cancer Chemother Pharmacol. 1999;44(4):312-8. PubMed PMID: 10447579.

84: Sparidans RW, Kettenes-van den Bosch JJ, van Tellingen O, Nuyen B, Henrar RE, Jimeno JM, Faircloth G, Floriano P, Rinehart KL, Beijnen JH. Bioanalysis of aplidine, a new marine antitumoral depsipeptide, in plasma by high-performance liquid chromatography after derivatization with trans-4-hydrazino-2-stilbazole. J Chromatogr B Biomed Sci Appl. 1999 Jun 11;729(1-2):43-53. PubMed PMID: 10410926.

85: Depenbrock H, Peter R, Faircloth GT, Manzanares I, Jimeno J, Hanauske AR. In vitro activity of aplidine, a new marine-derived anti-cancer compound, on freshly explanted clonogenic human tumour cells and haematopoietic precursor cells. Br J Cancer. 1998 Sep;78(6):739-44. PubMed PMID: 9743292; PubMed Central PMCID: PMC2062976.

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88: Urdiales JL, Morata P, Núñez De Castro I, Sánchez-Jiménez F. Antiproliferative effect of dehydrodidemnin B (DDB), a depsipeptide isolated from Mediterranean tunicates. Cancer Lett. 1996 Apr 19;102(1-2):31-7. PubMed PMID: 8603376.