Skip to main content

Advertisement

SpringerLink
Log in

Second-generation taxanes effectively suppress subcutaneous rat lymphoma: role of disposition, transport, metabolism, in vitro potency and expression of angiogenesis genes

  • PRECLINICAL STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

The study investigated possible mechanisms by which second-generation taxanes, established as significantly more effective than paclitaxel in vitro, suppress a rat lymphoma model in vivo. The studied mechanisms included taxane pharmacokinetics, expression of genes dominating their metabolism (Cyp3a1/2) and transport (Abcb1) and genes controlling tumour angiogenesis (growth factors and receptors). SB-T-1214, SB-T-12854 and IDN5109 suppressed rat lymphoma more effectively than paclitaxel, SB-T-12851, SB-T-12852, SB-T-12853 or IDN5390 as well as P388D1 leukaemia cells in vitro. The greater anti-lymphoma effects of SB-T-1214 in rats corresponded to a higher bioavailability than with SB-T-12854, and lower systemic toxicity of SB-T-1214 for rats reflected its lower cytotoxicity for P388D1 cells in vitro. Suppression of Abcb1 and CYP3a1 expression by SB-T-1214 and IDN5109 could partly explain their anti-lymphoma effects, but not that of SB-T-12854. Growth factors genes Egf, Fgf, Pdgf, and Vegf associated with tumour angiogenesis had significantly lower expression following treatment with anti-lymphoma effective IDN5109 and their receptors were unaffected, whereas inefficient IDN5390 increased expression of the most important Vegf. The effective SB-T-12854 inhibited Egf, Egfr, Fgfr and Pdgfr expression, while the ineffective SB-T-12851, SB-T-12852 and SB-T-12853 inhibited only Egf or Egfr expression. Vegfr expression was inhibited significantly by SB-T-12851 and SB-T-12854, but effect of SB-T-12851 was compromised by induced Vegf expression. The very effective SB-T-1214 decreased the expression of Vegf, Egf and all receptors most prominently indicating the possible supporting role of these genes in anti-lymphoma effects. In conclusion, SB-T-1214, SB-T-12854 and IDN5109 are good candidates for further study.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

Egf:

Epidermal

Fgf:

Fibroblast

Pdgf:

Platelet-derived

Vegf:

Vascular endothelial

 :

Their receptors Egfr, Fgfr, Pdgfr, and Vegfr

References

  1. Galleti E, Magnani M, Renzulli ML, Botta M (2007) Paclitaxel and docetaxel resistance: molecular mechanisms and development of new generation taxanes. Chem Med Chem 2:920–942

    Google Scholar 

  2. Otová B, Václavíková R, Danielova V, Holubová J, Ehrlichová M, Horský S et al (2006) Effects of paclitaxel, docetaxel and their combinations on subcutaneous lymphomas in inbred Sprague-Dawley/Cub rats. Eur J Pharm Sci 29:442–450

    Article  PubMed  Google Scholar 

  3. Kovář J, Ehrlichová M, Šmejkalová B, Zanardi I, Ojima I, Gut I (2009) Comparison of Cell Death-inducing Effect of Novel Taxane SB-T-1216 and Paclitaxel in Breast Cancer Cells. Anticancer Res 29:2951–2960

    PubMed  Google Scholar 

  4. Gallagher H, Carroll WM, Dowd M, Rochev Y (2008) The effects of vinblastine on endothelial cells. Endothelium 15:9–15

    Article  PubMed  CAS  Google Scholar 

  5. Ehrlichová M, Václavíkova R, Ojima I, Wu X, Kuznetsova LV et al (2005) Transport and cytotoxicity of paclitaxel, docetaxel and three novel taxanes in human breast cancer cells. N-S Arch Pharmacol 372:95–105

    Article  Google Scholar 

  6. Gut I, Danielová V, Holubová J, Souček P, Klučková H (2000) Cytotoxicity of cyclophosphamide, paclitaxel and docetaxel for tumor cell lines in vitro: effects of concentration, time and CYP-catalyzed metabolism. Arch Toxicol 74:437–446

    Article  PubMed  CAS  Google Scholar 

  7. Freedman H, Huzil JT, Luchko T, Luduena RF, Tuzsynski JA (2009) Identification and characterization of an intermediate taxol binding site within microtubule nanopores and a mechanism for tubulin isotype binding selectivity. J Chem Inf Model 49:424–436

    Article  PubMed  CAS  Google Scholar 

  8. Gut I, Ojima I, Vaclavikova R, Simek P, Horsky S, Linhart I, Soucek P et al (2006) Metabolism of new-generation taxanes in human, pig, minipig and rat liver microsomes. Xenobiotica 36:772–792

    Article  PubMed  CAS  Google Scholar 

  9. Beer M, Lenaz L, Amador D (2008) Phase II study of ortataxel in taxane-resistant breast cancer. J Clin Oncol 26:20, supplement, abstract 1066

    Article  Google Scholar 

  10. Tortora G, Caputo R, Damiano V, Fontanini G, Melisi D et al (2001) Oral administration of a novel taxane, an antisense oligonucleotide targeting protein kinase A, and the epidermal growth factor receptor inhibitor Iressa causes cooperative antitumor and antiangiogenic activity. Clin Cancer Res 7:4156–4163

    PubMed  CAS  Google Scholar 

  11. Ferlini C, Raspaglio G, Mozzetti S, Cicchillitti L, Filippetti F et al (2005) The seco-taxane IDN5390 is able to target class III beta-tubulin and to overcome paclitaxel resistance. Cancer Res 65:2397–2405

    Article  PubMed  CAS  Google Scholar 

  12. Otová B, Sladká M, Damoiseaux J, Panczak A, Mandys V, Marinov I (2002) Relevant animal model of human lymphoblatic leukaemia/lymphoma—spontaneous T- Cell lymphomas in an inbred sprague-dawley rat strain (SD/Cub) - review. Folia Biologica (Praha) 48:213–226

    Google Scholar 

  13. Soufla G, Sifakis S, Baritaki S, Zafiropulos A, Koumantakis E, Spandidos DA (2005) VEGF, FGF2, TGFB1 and TGFBR1 mRNA expression levels correlate with the malignant transformation of the uterine cervix. Cancer Lett 18:105–118

    Article  Google Scholar 

  14. Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257

    Article  PubMed  CAS  Google Scholar 

  15. Dong X, Han ZC, Yang R (2007) Angiogenesis and antiangiogenic therapy in hematologic malignancies. Crit Rev Oncol Hematol 62:105–118

    Article  PubMed  Google Scholar 

  16. Ojima I, Slater JC, Michaud KSD, Bounaud PY et al (1996) Syntheses and structure-activity relationships of the second generation antitumor taxoids. Exceptional activity against drug-resistant cancer cells. J Med Chem 39:3889–3896

    Article  PubMed  CAS  Google Scholar 

  17. Carrabin N, Mithieux F, Meeus P, Trédan O, Guastalla JP, Bachelot T et al (2010) Hyperthermic intraperitoneal chemotherapy with oxaliplatin and without adjuvant chemotherapy in stage IIIC ovarian cancer. Bull Cancer 97:E23–E32

    PubMed  CAS  Google Scholar 

  18. Ripley RT, Davis JL, Kemp CD, Steinberg SM, Toomey MA, Avital I (2010) Prospective randomized trial evaluating mandatory second look surgery with HIPEC and CRS vs. standard of care in patients at high risk of developing colorectal peritoneal metastases. Trials 11:62

    Article  PubMed  Google Scholar 

  19. Yeh YC, McDonnell A, Klinger EV, Fowler B, Matta L, Voit D, Reddy P (2010) Comparison of healthcare resource use between patients receiving ondansetron or palonosetron as prophylaxis for chemotherapy-induced nausea and vomiting. J Oncol Pharm Pract 2010 May 7 [Epub ahead of print]

  20. Vredenburg MR, Ojima I, Veith J, Pera P et al (2001) Effects of orally-active taxanes on p-glycoprotein modulation and colon and breast carcinoma drug resistance. J Natl Cancer Inst 93:1234–1245

    Article  PubMed  CAS  Google Scholar 

  21. Ojima I, Slater JC, Kuduk SD, Takeuchi CS, Gimi RH et al (1997) Syntheses and structure-activity relationships of taxoids derived from 14β-Hydroxy-10-deacetylbaccatin III. J Med Chem 40:267–278

    Article  PubMed  CAS  Google Scholar 

  22. Taraboletti G, Micheletti G, Rieppi M, Poli M, Turatto M et al (2002) Antiangiogenic and antitumor activity of IDN5390, a new taxane derivative. Clin Cancer Res 8:1182–1188

    PubMed  CAS  Google Scholar 

  23. Tomayko MM, Reynolds CP (1989) Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol 24:148–154

    Article  PubMed  CAS  Google Scholar 

  24. Souček P, Anzenbacher P, Skoumalová I, Dvořák M (2005) Expression of cytochrome P450 genes in CD34+ hematopoietic stem and progenitor cells. Stem Cells 23:1417–1422

    Article  PubMed  Google Scholar 

  25. Sano D, Matsuda H, Ishiguro Y, Nishimura G, Kawakami M, Tsukuda M (2006) Antitumor effects of IDN5109 on head and neck squamous cell carcinoma. Oncol Rep 15:329–334

    PubMed  CAS  Google Scholar 

  26. Ehrlichova M, Koc M, Truksa J, Naldova Z, Vaclavikova R, Kovar J (2005) Cell death induced by taxanes in breast cancer cells: cytochrome c is released in resistant but not in sensitive cells. Anticancer Res 25:4215–4224

    PubMed  CAS  Google Scholar 

  27. Loos WJ, Baker SD, Verweij J, Boonstra JG, Spareboom A (2003) Clinical pharmacokinetics of unbound docetaxel: role of polysorbate 80 and serum proteins. Clin Pharmacol Ther 74:364–371

    Article  PubMed  CAS  Google Scholar 

  28. Ojima I (2008) Guided molecular missiles for tumor-targeting chemotherapy-case studies using the second-generation taxoids as warheads. Acc Chem Res 41:108–119, Epub 2007 Jul 31

    Article  PubMed  CAS  Google Scholar 

  29. Vaclavikova R, Nordgard SH, Alnaes GIG, Hubackova M, Kubala E, Kodet R et al (2008) Single nucleotide polymorphisms in the multidrug resistance gene 1 (ABCB1); effects on its expression and clinico-pathological characteristics in breast cancer patients. Pharmacogenet Genomics 18:263–273

    Article  PubMed  CAS  Google Scholar 

  30. Cébe-Suarez S, Zehnder-Fjällman A, Ballmer-Hofer K (2006) The role of VEGF receptors in angiogenesis; complex partnerships. Cell Mol Life Sci 63:601–615

    Article  PubMed  Google Scholar 

  31. Shibuya M, Claesson-Welsh L (2006) Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res 312:549–560

    Article  PubMed  CAS  Google Scholar 

  32. Cassinelli G, Lanzi C, Supino R, Pratesi G et al (2002) Cellular bases of antitumor activity of the novel taxane IDN 5109 (BAY59-8862) on hormone-refractory prostate cancer. Clin Cancer Res 8:2647–2654

    PubMed  CAS  Google Scholar 

  33. Gutowska I, Baranowska-Bosiacka I, Baśkiewicz M, Milo B, Siennicka A et al (2010) Fluoride as a pro-inflammatory factor and inhibitor of ATP bioavailability in differentiated human THP1 monocytic cells. Toxicol Lett 196:74–9, Epub 2010 Apr 22

    Article  PubMed  CAS  Google Scholar 

  34. Vobořilová J, Němcová V, Neubauerová J, Ojima I, Gut I, Kovář J (2009) Cell death induced by novel fluorinated taxanes in sensitive and resistant cancer cells. Invest New Drugs 2009; Published on line 16 December 2009, doi:10.1007/s10637-009-9368-8

  35. Jasmine Zain and Owen A. O’Connor (2010) Targeting histone deacetyalses in the treatment of B- and T-cell malignancies Invest New Drugs. 2010 December; 28(Suppl 1): 58–78 Published online 2010 December 4. doi:10.1007/s10637-010-9591-3.

  36. Ojima I, Chen J, Sun L, Borella CP, Wang T, Miller ML, Lin S, Geng X, Kuznetsova L, Qu C, Gallager D, Zhao X, Zanardi I, Xia S, Horwitz SB, Mallen-St. Clair J, Guerriero JL, Bar-Sagi D, Veith JM, Pera P, Bernacki RJ (2008) Design, Synthesis and Biological Evaluation of New Generation Taxoids. J Med Chem 51:3203–3221

    Article  PubMed  CAS  Google Scholar 

  37. Pepe A, Kuznetsova L, Sun L, Ojima I (2009) Fluoro-taxoid anticancer agents. In: Ojima I (ed) Fluorine in medicinal chemistry and chemical biology. Wiley-Blackwell, Chichester, pp 117–139

    Chapter  Google Scholar 

  38. Bobková K, Otová B, Murinov I, Mandys V, Panczak A, Votruba I, Holý A (2000) Anticancer effect of PMEDAP – monitoring of apoptosis. Anticancer Res 20:1041–1048

    PubMed  Google Scholar 

Download references

Acknowledgements

Financial support: Internal Grant Agency, Czech Ministry of Health, grant No.9803-3 (to I.G., R.V., M.E., P.S. and S.H.), Project VZ 0021620808, Czech Ministry of Education, Youth & Sports (to B.O. and J.H.), Czech Grant Agency GACR grant No. 301/09/0362 (to J.K., V.N. and J.V.) and N.C.I., U. S. A. (CA103314 to I.O. & I.Z.).

I.G., B.O., R.V., and I.O contributed to design, execution and analysis of experiments and writing of the manuscript, M.S., P.S., S.H., J.K., V.N., J.V., and J.H. contributed to execution and analysis of data and I.Z. synthesized the taxanes.

Conflict of interest statement

There is no conflict of interest in terms of funding (scientific grants only), stock-holding, and all the chemicals were either purchased as declared in Methods. Second-generation taxanes were developed, synthesized and provided by Professor Ojima who is the co-author of the manuscript.

Author information

Authors and Affiliations

  1. Institute of Biology and Medical Genetics, 1st Faculty of Medicine and General Teaching Hospital Charles University, 128 00, Prague, Czech Republic

    Berta Otová & Jiří Hrdý

  2. Institute of Chemical Biology & Drug Discovery, State University of New York at Stony Brook, New York, NY, USA

    Iwao Ojima & Ilaria Zanardi

  3. Toxicogenomics Unit, National Institute of Public Health, 100 42, Prague, Czech Republic

    Radka Václavíková, Marie Ehrlichová, Pavel Souček, Stanislav Horský & Ivan Gut

  4. Department of Cell and Molecular Biology, 3rd Faculty of Medicine, Charles University Prague, Prague, Czech Republic

    Jana Vobořilová, Vlasta Němcová & Jan Kovář

  5. Centre of Laboratory Activities, National Institute of Public Health, 100 42, Prague 10, Czech Republic

    Ivan Gut

Authors
  1. Berta Otová
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Iwao Ojima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Radka Václavíková
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiří Hrdý
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marie Ehrlichová
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pavel Souček
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jana Vobořilová
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Vlasta Němcová
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ilaria Zanardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Stanislav Horský
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jan Kovář
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ivan Gut
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ivan Gut.

Electronic supplementary materials

Below is the link to the electronic supplementary material.

ESM 1

(JPEG 108 kb)

High resolution image file (TIFF 496 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Otová, B., Ojima, I., Václavíková, R. et al. Second-generation taxanes effectively suppress subcutaneous rat lymphoma: role of disposition, transport, metabolism, in vitro potency and expression of angiogenesis genes. Invest New Drugs 30, 991–1002 (2012). https://doi.org/10.1007/s10637-011-9654-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-011-9654-0

Keywords

Search

Navigation