Abstract
Neuroblastoma, the most common extracranial solid tumour in children, may undergo spontaneous differentiation or regression, but the majority of metastatic neuroblastomas have poor prognosis despite intensive treatment. Retinoic acid regulates growth and differentiation of neuroblastoma cells in vitro, and has shown activity against human neuroblastomas in vivo. The retinoid 9-cis RA has been reported to induce apoptosis in vitro, and to inhibit the growth of human neuroblastoma xenografts in vivo. However, at given dosage, the treatment with 9-cis RA caused significant toxic side effects. In the present study we investigated the bioavailability of 9-cis RA in rat. In addition, we compared two different dose schedules using 9-cis RA. We found that a lower dose of 9-cis RA (2 mg day−1) was non-toxic, but showed no significant effect on tumour growth. The bioavailability of 9-cis RA in rat was 11% and the elimination half-life (t1/2) was 35 min. Considering the short t1/2, we divided the toxic, but tumour growth effective dose 5 mg day−1 into 2.5 mg p.o. twice daily. This treatment regimen showed no toxicity but only limited effect on tumour growth. Our results suggest that 9-cis RA may only have limited clinical significance for treatment of children with poor prognosis neuroblastoma. © 2001 Cancer Research Campaign http://www.bjcancer.com
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Abemayor E (1992) The effects of retinoic acid on the in vitro and in vivo growth of neuroblastoma cells. Laryngoscope 102: 1133–1149
Anzano MA, Byers SW, Smith JM, Peer CW, Mullen LT, Brown CC, Roberts AB and Sporn MB (1994) Prevention of breast cancer in the rat with 9-cis-retinoic acid as a single agent and in combination with tamoxifen. Cancer Res 54: 4614–4617
Biedler JL, Helson L and Spengler BA (1973) Morphology and growth, tumorigenicity, and cytogenetics of human neuroblastoma cells in continuous culture. Cancer Res 33: 2643–2652
Disdier B, Bun H, Catalin J and Durand A (1996) Simultaneous determination of all-trans-, 13-cis-, 9-cis-retinoic acid and their 4-oxo-metabolites in plasma by high-performance liquid chromatography. J Chromatogr B Biomed Appl 683: 143–154
Disdier B, Marchetti MN, Bun H, Placidi M and Durand A (2000) Kinetics of plasma and tissue distribution of 9-cis-retinoic acid in rat. Skin Pharmacol Appl Skin Physiol 13: 9–16
Eckhoff C, Bailey JR, Collins MD, Slikker W Jr. and Nau H (1991) Influence of dose and pharmaceutical formulation of vitamin A on plasma levels of retinyl esters and retinol and metabolic generation of retinoic acid compounds and beta-glucuronides in the cynomolgus monkey. Toxicol Appl Pharmacol 111: 116–127
Heyman RA, Mangelsdorf DJ, Dyck JA, Stein RB, Eichele G, Evans RM and Thaller C (1992) 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 68: 397–406
Howell SR, Shirley MA and Ulm EH (1998) Effects of retinoid treatment of rats on hepatic microsomal metabolism and cytochromes P450. Correlation between retinoic acid receptor/retinoid × receptor selectivity and effects on metabolic enzymes. Drug Metab Dispos 26: 234–239
Kohler JA, Imeson J, Ellershaw C and Lie SO (2000) A randomized trial of 13-Cis retinoic acid in children with advanced neuroblastoma after high-dose therapy. Br J Cancer 83: 1124–1127
Lanvers C, Hempel G, Blaschke G and Boos J (1996) Simultaneous determination of all-trans-, 13-cis- and 9-cis-retinoic acid, their 4-oxo metabolites and all-trans-retinol in human plasma by high-performance liquid chromatography. J Chromatogr B Biomed Appl 685: 233–240
Lefebvre P, Agadir A, Cornic M, Gourmel B, Hue B, Dreux C, Degos L and Chomienne C (1995) Simultaneous determination of all-trans and 13-cis retinoic acids and their 4-oxo metabolites by adsorption liquid chromatography after solid-phase extraction. J Chromatogr B Biomed Appl 666: 55–61
Lovat PE, Irving H, Annicchiarico-Petruzzelli M, Bernassola F, Malcolm AJ, Pearson AD, Melino G and Redfern CP (1997) Apoptosis of N-type neuroblastoma cells after differentiation with 9-cis-retinoic acid and subsequent washout. J Natl Cancer Inst 89: 446–452
Matthay KK and Reynolds CP (2000) Is there a role for retinoids to treat minimal residual disease in neuroblastoma?. Br J Cancer 83: 1121–1123
Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, Swift P, Shimada H, Black CT, Brodeur GM, Gerbing RB and Reynolds CP (1999) Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med 341: 1165–1173
Nilsson S, Pahlman S, Arnberg H, Letocha H and Westlin JE (1993) Characterization and uptake of radiolabelled meta-iodobenzylguanidine (MIBG) in a human neuroblastoma heterotransplant model in athymic rats. Acta Oncol 32: 887–891
Ponthan F, Borgstrom P, Hassan M, Wassberg E, Redfern CP and Kogner P (2001) The vitamin A analogues: 13-cis retinoic acid, 9-cis retinoic acid, and Ro 13-6307 inhibit neuroblastoma tumour growth in vivo. Med Pediatr Oncol 36: 127–131
Redfern CP, Lovat PE, Malcolm AJ and Pearson AD (1995) Gene expression and neuroblastoma cell differentiation in response to retinoic acid: differential effects of 9-cis and all-trans retinoic acid. Eur J Cancer 31: 486–494
Reynolds CP, Kane DJ, Einhorn PA, Matthay KK, Crouse VL, Wilbur JR, Shurin SB and Seeger RC (1991) Response of neuroblastoma to retinoic acid in vitro and in vivo. Prog Clin Biol Res 366: 203–211
Shirley MA, Bennani YL, Boehm MF, Breau AP, Pathirana C and Ulm EH (1996) Oxidative and reductive metabolism of 9-cis-retinoic acid in the rat. Identification of 13,14-dihydro-9-cis-retinoic acid and its taurine conjugate. Drug Metab Dispos 24: 293–302
Sidell N (1982) Retinoic acid-induced growth inhibition and morphologic differentiation of human neuroblastoma cells in vitro. J Natl Cancer Inst 68: 589–596
Sucov HM and Evans RM (1995) Retinoic acid and retinoic acid receptors in development. Mol Neurobiol 10: 169–184
Wassberg E, Pahlman S, Westlin JE and Christofferson R (1997) The angiogenesis inhibitor TNP-470 reduces the growth rate of human neuroblastoma in nude rats. Pediatr Res 41: 327–333
United Kingdom Co-ordinating Committee on Cancer Research (UKCCCR) (1998) Guidelines for the Welfare of Animals in Experimental Neoplasia (Second Edition). Br J Cancer 77: 1–10
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Ponthan, F., Kogner, P., Bjellerup, P. et al. Bioavailability and dose-dependent anti-tumour effects of 9-cis retinoic acid on human neuroblastoma xenografts in rat. Br J Cancer 85, 2004–2009 (2001). https://doi.org/10.1054/bjoc.2001.2186
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2001.2186