Abstract
Features of temozolomide
Temozolomide (TMZ) belongs to the imidazotetrazine class and it is a DNA-methylating agent that has a good antitumor activity. Despite of dacarbazine, TMZ is spontaneously converted into its active metabolite 5-(3-methyltriazen-l-yl)imidazole-4-carboxamide at physiologic pH, so it is not required in enzymatic demethylation in the liver. TMZ is able to cross the blood brain barrier and is stable at gastric acid pH so it has almost 100% oral bioavailability and is rapidly absorbed after it is taken orally.
Temozolomide in cancer patients
On the basis of the relatively safe toxicity and the findings achieved in adult malignant gliomas, phase I and II clinical trials were set up to evaluate the opportunity of using this novel drug in pediatric cancer, too. In this review, we evaluate the antitumor activity of TMZ against high-grade gliomas, low-grade-gliomas, and medulloblastoma/primitive neuroectodermal tumors analyzing several phases I and II clinical trials in children.
Conclusions
In spite of the poor activity of TMZ against pediatric brain tumors, the use of the drug in combination with other compounds should be evaluated in phases I and II clinical trials. Moreover, the evaluation of the methylation status of the O6-methylguanine DNA methyltransferase promoter in glioblastoma biopsy specimens could be assayed as a predictive factor of TMZ efficacy.
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References
Baldwin RT, Preston-Martin S (2004) Epidemiology of brain tumors in childhood—a review. Toxicol Appl Pharmacol 199:118–131
Epstein SS, Ashford NA, Blackwelder B, Castleman B, Cohen G, Goldsmith E, Mazzocchi A, Young QD (2002) The crisis in U.S. and international cancer policy. Int J Health Serv 32:669–707
Stevens MF, Hickman JA, Langdon SP, Chubb D, Vickers L, Stone R, Baig G, Goddard C, Gibson NW, Slack JA (1987) Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res 47:5846–5852
Stevens MF, Hickman JA, Stone R, Gibson NW, Baig GU, Lunt E, Newton CG (1984) Antitumor imidazotetrazines: 1, synthesis and chemistry of 8-carboyl-3-(2-chloethyl)imidazo[5,1-d-]-1,2,3,5-tetrazin-4(3 H)-one, a novel broad spectrum antitumor agent. J Med Chem 27:196–201
Moore MJ, Feld R, Hedley D, Oza A, Siu LL (1998) A phase II study of temozolomide in advanced untreated pancreatic cancer. Invest New Drugs 16:77–79
Stupp R, Gander M, Leyvraz S, Newlands E (2001) Current and future developments in the use of temozolomide for the treatment of brain tumours. Lancet Oncol 2:552–560
Patel M, McCully C, Godwin K, Balis F (2003) Plasma and cerebrospinal fluid pharmacokinetics of intravenous temozolomide in non-human primates. J Neurooncol 61:203–207
Nicholson HS, Krailo M, Ames MM, Seibel NL, Reid JM, Liu-Mares W, Vezina LG, Ettinger AG, Reaman GH (1998) Phase I study of temozolomide in children and adolescent with recurrent solid tumors: a report from the Children’s Cancer Group. J Clin Oncol 16:3037–3043
Riccardi A, Mazzarella G, Cefalo G, Garre ML, Massimino M, Barone C, Sandri A, Ridola V, Ruggiero A, Mastrangelo S, Lazzareschi I, Caldarelli M, Maira G, Madon E, Riccardi R (2003) Pharmacokinetics of temozolomide given three times a day in pediatric and adult patients. Cancer Chemother Pharmacol 52:459–464
Bleehen NM, Newlands ES, Lee SM, Thatcher LN, Selby P, Calvert AH, Rustin GJ, Brampton M, Stevens MF (1995) Cancer research campaign phase II trial of temozolomide in metastatic melanoma. J Clin Oncol 13:910–913
Bower M, Newlands ES, Lee SM, Thatcher LN, Selby P, Calvert AH, Rustin GJ, Brampton M, Stevens MF (1997) Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma. Cancer Chemother Pharmacol 40:484–488
Gibson NW, Hickman JA, Erickson LC (1985) DNA cross-linking and cytotoxicity in normal and transformed human cells treated in vitro with 8-carbamoyl-3-(2-chloroethyl)imidazo [5,1-d ]1,2,3,5-tetrazin-4(3H)-one. Cancer Res 44:1772–1779
Wedge SR, Porteus JK, May BL, Newlands ES (1996) Potentization of temozolomide and BCNU cytotoxicity by O(6)-benzylguanine: a comparative study in vitro. Br J Cancer 73:482–490
Middlemas DS, Stewart CF, Kirstein MN, Poquette C, Friedman HS, Houghton PJ, Brent TP (2000) Biochemical correlates of temozolomide sensitivity in pediatric solid tumor xenograft models. Clin Cancer Res 6:998–1007
Wedge SR, Porteous JK, Newlands ES (1996) 3-aminobenzamide and/or O6-benzylguanine evaluated as an adjuvant to temozolomide BCNU treatment in cell lines of variable mismatch repair status and O6-alkylguanine-DNA alkyltransferase activity. Br J Cancer 74:1030–1036
Newlands ES, Blackledge GR, Slack JA, Rustin GJ, Smith DB, Stuart NS (1992) Phase I trial of temozolomide. Br J Cancer 65:287–291
Yung WK, Prados MD, Yaya-Tur R, Rosenfeld SS, Brada M, Friedman HS, Albright R, Olson J, Chang SM, O’Neill AM, Friedman AH, Bruner J, Yue N, Dugan M, Zaknoen S, Levin VA (1999) Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse: Temodal Brain Tumor Group. J Clin Oncol 17:2762–2771
Osoba D, Brada M, Yung WK, Prados MD (2000) Health related quality of life in patients treated with temozolomide versus procarbazine for recurrent glioblastoma multiforme. J Clin Oncol 18:1481–1491
Quinn JA, Reardon DA, Friedman AH, Rich JN, Sampson JH, Provenzale JM, McLendon RE, Gururangan S, Bigner DD, Herndon JE 2nd, Avgeropoulos N, Finlay J, Tourt-Uhlig S, Affronti ML, Evans B, Stafford-Fox V, Zaknoen S, Friedman HS (2003) Phase II trial of temozolomide in patients with progressive low-grade glioma. J Clin Oncol 21:646–651
Estlin EJ, Lashford L, Ablett S, Price L, Gowing R, Gholkar A, Kohler J, Lewis IJ, Morland B, Pinkerton CR, Stevens MCG, Mott M, Stevens R, Newell DR, Walker D, Dicks Mireaux C, McDowell H, Reidenberg P, Statkevich P, Marco A, Batra V, Dugan M, Pearson ADJ (1998) Phase I study of temozolomide in pediatric patients with advanced cancer. United Kingdom Children’s Cancer study group. Br J Cancer 78:652–661
Lashford LS, Thiesse P, Jouvet A, Jaspan T, Couanet D, Griffiths PD, Doz F, Ironside J, Robson K, Hobson R, Dugan M, Pearson AD, Vassal G, Frappaz D (2002) Temozolomide in Malignant gliomas of childhood: a United Kingdom children’s cancer study group and French society for pediatric oncology intergroup study. J Clin Oncol 20:4684–4691
Verschuur AC, Grill J, Lelouch-Tubiana A, Couanet D, Kalifa C, Vassal G (2004) Temozolomide in pediatric high-grade glioma: a key for combination therapy? Br J Cancer 91:425–429
Broniscer A, Iacono L, Chintagumpala M, Fouladi M, Wallace D, Bowers DC, Stewart C, Krasin MJ, Gajjar A (2005) Role of temozolomide after radiotherapy for newly diagnosed diffuse brainstem glioma in children: results of a multiinstitutional study (SJHG-98) Cancer 103:133–139
Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003
Kuo DJ, Weiner HL, Wisoff J, Miller DC, Knopp EA, Finlay JL (2003) Temozolomide is active in childhood, progressive unresectable, low-grade gliomas. J Pediatr Hematol Oncol 25:372–378
Aryan HE, Meltzer HS, Lu DC, Ozgur BM, Levy ML, Bruce DA (2005) Management of pilocytic astrocytoma with diffuse leptomeningeal spread: two cases and review of the literature. Childs Nerv Syst 21:477–481
van Rijn J, Heimans JJ, van den Berg J, van der Valk P, Slotman BJ (2000) Survival of human glioma cells treated with various combination of temozolomide and X-rays. Int J Radiat Onc Biol Phys 47:779–784
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996
Friedman HS, Petros WP, Friedman AH, Schaaf LJ, Kerby T, Lawyer J, Parry M, oughton PJ, Lovell S, Rasheed K, Cloughsey T, Stewart ES, Colvin OM, Provenzale JM, McLendon RE, Bigner DD, Cokgor I, Haglund M, Rich J, Ashley D, Malczyn J, GL, Elfring Miller LL (1999) Irinotecan therapy in adults with recurrent or progressive malignant glioma. J Clin Oncol 17:1516–1525
Houghton PJ, Stewart CF, Cheshire PJ, Richmond LB, Kirstein MN, Poquette CA, Tan M, Friedman HS, Brent TP (2000) Antitumor activity of temozolomide combined with irinotecan is partly independent of O6-methylguanine-DNA-methyltranferase and mismatch repair phenotypes in xenograft models. Clin Cancer Res 6:4110–4118
Silvani A, Eoli M, Salmaggi A, Lamperti E, Maccagnano E, Broggi G, Boiardi A (2004) Phase II trial of cisplatin plus temozolomide, in recurrent and progressive malignant glioma patients. J Neurooncol 66:203–208
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Barone, G., Maurizi, P., Tamburrini, G. et al. Role of temozolomide in pediatric brain tumors. Childs Nerv Syst 22, 652–661 (2006). https://doi.org/10.1007/s00381-006-0081-z
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DOI: https://doi.org/10.1007/s00381-006-0081-z