Skip to main content

Advertisement

SpringerLink
Log in

Murine toxicology and pharmacokinetics of novel retinoic acid metabolism blocking agents

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Novel potent C-4 azolyl retinoic acid metabolism blocking agents (RAMBAs)—VN/14-1, VN/50-1, VN/66-1, VN/67-1, and VN/69-1, have been synthesized and investigated for their in vitro and in vivo effects against breast and prostate cancers. These RAMBAs, in addition to being potent inhibitors of all-trans-retinoic acid (ATRA) metabolism have potent anti-cancer properties and in vivo anti-tumor efficacies as characterized in breast and prostate cancer models. Here we determined the toxicity and pharmacokinetics (PK) of these various RAMBAs.

Methods

Preliminary acute toxicity studies of these RAMBAs were carried out using Swiss NIH mice. The toxicity profile of the RAMBAs was evaluated relative to ATRA. Three different doses (8.3, 33, and 100 μmol/kg/day) of ATRA and RAMBAs were administered on a daily basis subcutaneously for 14 days to the mice. Clinical signs of toxicity alopecia, scaly skin, and loss of body weight in the mice were observed during the study and the maximum tolerated dose was determined. PK of selected agents (VN/14-1, VN/50-1, and VN/66-1) was studied in Balb/C mice after a single dose subcutaneous administration. Plasma concentrations of the agents were quantitatively determined using a high-performance liquid chromatographic method with ultraviolet detection. Plasma concentration versus time profiles were fit to various PK structural models and relevant PK parameters were estimated.

Results

VN/66-1 and VN/69-1 were found to be the least toxic even at the highest doses when compared to the other RAMBAs and ATRA. VN/66-1 had the longest half-life, the slowest clearance, and the greatest exposure.

Conclusions

Based on PK characteristics and toxicity studies, VN/66-1 appeared to be the most favorable agent. However, both VN/14-1 and VN/66-1 are our leads based on the fact that VN/14-1 has been found to be highly effective in endocrine-sensitive and -resistant breast cancer cells and tumors with little toxicity. Our findings provide valuable information that will be used to select RAMBAs and establish therapeutic regimens that provide optimal efficacy with minimal toxicity.

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

Similar content being viewed by others

References

  1. Adams J (1993) Structure-activity and dose-response relationships in the neural and behavioral teratogenesis of retinoids. Neurotoxicol Teratol 15:193–202

    Article  PubMed  CAS  Google Scholar 

  2. Altucci L, Gronemeyer H (2001) The promise of retinoids to fight against cancer. Nat Rev Cancer 1:181–193

    Article  PubMed  CAS  Google Scholar 

  3. Belosay A, Njar VCO, Brodie AMH (2006) Effects of novel retinoic acid metabolism blocking agent (VN/14-1) on letrozole insensitive breast cancer cells. Cancer Res 66:11489–11493

    Article  Google Scholar 

  4. Bollag W (1975) Therapy of epithelial tumors with aromatic retinoic acid analog. Chemotherapy 21:236–247

    Article  PubMed  CAS  Google Scholar 

  5. Boyle JO (2001) Retinoids mechanisms and cyclins. Curr Oncol Rep 3:301–305

    Article  PubMed  CAS  Google Scholar 

  6. Cohen M (1993) Terinoin: a review of preclinical toxicological studies. Drug Dev Res 30:244–251

    Article  CAS  Google Scholar 

  7. Dragnev KH, Rigas JR, Dmitrovsky E (2000) The retinoids and cancer prevention mechanisms. Oncologist 5:361–368

    Article  PubMed  CAS  Google Scholar 

  8. Fontana JA, Rishi AK (2002) Classical and novel retinoids: their targets in cancer therapy. Leukemia 16:463–472

    Article  PubMed  CAS  Google Scholar 

  9. Freemantle S, Spinella MJ, Dmitrovsky E (2003) Retinoids in cancer therapy and chemoprevention: promise meets resistance. Oncogene 22:7305–7315

    Article  PubMed  CAS  Google Scholar 

  10. Herr RJ (2002) 5-Substituted-1H-tetrazoles as carboxylic acid isosteres: medicinal chemistry and synthetic methods. Bioorg Med Chem 10:3379–3393

    Article  PubMed  CAS  Google Scholar 

  11. Huynh CK, Brodie AM, Njar VCO (2006) Inhibitory effects of retinoic acid metabolism blocking agents (RAMBAs) on the growth of human prostate cancer cells and LNCaP prostate tumour xenografts in SCID mice. Br J Cancer 94:513–523

    Article  PubMed  CAS  Google Scholar 

  12. Lindamood III C, Giles HD, Hill DL (1987) Preliminary toxicology profile of arotinoids SMR-2 and SMR-6 in male B6D2F1 mice. Fundam Appl Toxicol 8:517–530

    Article  PubMed  CAS  Google Scholar 

  13. Lindamood III C, Cope FO, Dillehay DL, Everson MP, Giles HD, Lamon EW, McCarthy DJ, Sartin JL, Hill DL (1990) Pharmacological and toxicological properties of carotinoids SMR-2 and SMR-6 in mice. Fundam Appl Toxicol 14:15–29

    Article  PubMed  CAS  Google Scholar 

  14. Le Doze F, Debruyne D, Albessard F, Barre L, Defer GL (2000) Pharmacokinetics of all-trans retinoic acid, 13-cis retinoic acid, and fenretinide in plasma and brain of rat. Drug Metab Dispos 28:205–208

    PubMed  CAS  Google Scholar 

  15. Miller W (1998) The emerging role of retinoids and retinoic acid metabolism blocking agents in the treatment of cancer. Cancer 83:1471–1482

    Article  PubMed  CAS  Google Scholar 

  16. Njar VCO, Nnane IP, Brodie AM (2000) Potent inhibitors of retinoic acid metabolism enzyme(s) by novel azolyl retinoids. Bioorg Med Chem Lett 10:1905–1908

    Article  PubMed  CAS  Google Scholar 

  17. Njar VCO (2002) Cytochrome p450 retinoic acid 4-hyroxylase inhibitors: potential agents for cancer therapy. Mini Rev Med Chem 2:261–269

    Article  PubMed  CAS  Google Scholar 

  18. Njar VCO, Gediya L, Purushottamachar P, Chopra P, Vasaitis TS, Khandelwal A, Mehta J, Huynh C, Belosay A, Patel J (2006) Retinoic acid metabolism blocking agents (RAMBAs) for treatment of cancer and dermatologic diseases. Bioorg Med Chem 14:4323–4340

    Article  PubMed  CAS  Google Scholar 

  19. Patel J B, Huynh CK, Handratta VD, Gediya LK, Brodie AM, Goloubeva OG, Clement OO, Nnane IP, Soprano DR, Njar VCO (2004) Novel retinoic acid metabolism blocking agents endowed with multiple biological activities are efficient growth inhibitors of human breast and prostate cancer cells in vitro and a human breast tumor xenograft in nude mice. J Med Chem 47:6716–6729

    Article  PubMed  CAS  Google Scholar 

  20. Patel JB, Mehta J, Belosay A, Sabins G, Khandelwal A, Brodie AMH, Njar VCO (2006) Novel retinoic acid metabolism blocking agents (RAMBAs) have potent inhibitory activities on human breast cancer cells and tumor growth. In review

  21. Staab HA (1962) Syntheses using heterocyclic amides (azolides). Angew Chem Internat Edit 1:351–367

    Article  Google Scholar 

  22. Ulukaya E, Wood E (1999) Fenretinide and its relation to cancer. Cancer Treat Rev 25:229–235

    Article  PubMed  CAS  Google Scholar 

  23. Vaezi MF, Alam M, Sani BP, Rogers TS, Simpson-Herren L, Wille JJ, Hill DL, Doran TI, Brouillette WJ, Muccio DD (1994) A conformationally defined 6-s-trans-retinoic acid isomer: synthesis, chemopreventive activity, and toxicology. J Med Chem 37:4499–4507

    Article  PubMed  CAS  Google Scholar 

  24. Van Heusden J, Borgerus M, Ramaekers F, Xhonneux B, Wouters W, De Coster R, Smets G (1996) Liarozole potentiates the all-trans-retinoic acid induced structural remodeling in human breast carcinoma MCF-7 cells in vitro. Eur J Cell Biol 71:89–98

    Google Scholar 

  25. Van Huesden J, Van Ginckel R, Bruwiere H, Moelans P, Janssen B, Floren W, Leede BJ, Van Dun J, Sanz G, Venet M, Dillen L, Van Hove C, Willemsens G, Janicot M, Wouters W (2002) Inhibition of all-trans-retinoic acid metabolism by R116010 induces antitumor activity. Br J Cancer 86:605–611

    Article  Google Scholar 

  26. Vasudevan J, Johnson AT, Huang D, Chandraratna RA. Compounds having activity as inhibitors of cytochrome P450A1. US Patent. 6,252,090. Other patents assigned to Allergan Sales Inc., include, US Patents 6,303,785 B1; 6,359,135 B1; 6,369,261 B1; 6,380,256 B1; 6,387,892 B1; 6,387,951 B1; 6,399,774 B1; 6,495,552 B2 and 531,599 B2

  27. William JB, Napoli JL (1986) Inhibition of retinoic acid metabolism by imidazole antimycotics in F9 embryonal carcinoma cells. Biochem Pharmacol 36:1386–1388

    Article  Google Scholar 

  28. Wouters W, Van Dun J, Dillen A, Coene M-C, Cools W, DeCoster R (1992) Effects of liarozole, a new antitumoral compound, on retinoic acid-induced inhibition of cell growth and on retinoic acid metabolism in MCF-7 human breast cancer cells. Cancer Res 52:2841–2846

    PubMed  CAS  Google Scholar 

  29. Wu C, Njar V, Brodie A, Borenstein M, Nnane I (2004) Quantification of a novel retinoic acid metabolism inhibitor, 4-(1H-imidazol-1-yl)retinoic acid (VN/14-1RA) and other retinoids in rat plasma by liquid chromatography with diode-array detection. J Chromato B Analyt Technol Biomed Life Sci 810:203–208

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Jyoti B. Patel

    Present address: Laboratory of Cancer Biology and Genetics, National Institute of Health, Bethesda, MD, USA

  2. Pankaj Chopra

    Present address: Department of Family Medicine, University of Missouri, Columbia, MO, USA

  3. Venkatesh D. Handratta

    Present address: Department of Psychiatry, University of Connecticut, Farmington, CT, USA

Authors and Affiliations

  1. Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD, 21201-1559, USA

    Jyoti B. Patel, Aakanksha Khandelwal, Pankaj Chopra, Venkatesh D. Handratta & Vincent C. O. Njar

  2. The University of Maryland Marlene and Stewart Greenebaum Cancer Center, School of Medicine, Baltimore, MD, 21201-1559, USA

    Vincent C. O. Njar

Authors
  1. Jyoti B. Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aakanksha Khandelwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pankaj Chopra
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Venkatesh D. Handratta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vincent C. O. Njar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vincent C. O. Njar.

Additional information

Jyoti B. Patel and Aakanksha Khandelwal contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Patel, J.B., Khandelwal, A., Chopra, P. et al. Murine toxicology and pharmacokinetics of novel retinoic acid metabolism blocking agents. Cancer Chemother Pharmacol 60, 899–905 (2007). https://doi.org/10.1007/s00280-007-0438-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-007-0438-3

Keywords

Search

Navigation