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Local delivery of temozolomide by biodegradable polymers is superior to oral administration in a rodent glioma model

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Abstract

Purpose

Dose-limiting adverse effects of thrombocytopenia and leukopenia prevent augmentation of current temozolomide (TMZ) dosing protocols; therefore, we hypothesized that the direct intracranial delivery of TMZ would lead to improved efficacy in an animal model of malignant glioma in an animal model.

Methods

Temozolomide was incorporated into biodegradable polymers and the active drug was released over 80 h. Intracranial toxicity was assessed in F344 rats and a maximally tolerated dose was not achieved.

Results

In vivo drug biodistribution demonstrated that intracranial concentrations of TMZ increased threefold compared with orally delivered TMZ. In a rodent glioma model, animals treated with a single TMZ polymer (50% w/w) had a median survival of 28 days (P < 0.001 vs. controls, P < 0.001 vs. oral treatment), whereas animals treated with oral TMZ had a median survival of 22 days compared to control animals (median survival of 13 days). Animals treated with two TMZ polymers (50% w/w) had a median survival of 92 days (P < 0.001 vs. controls, P < 0.001 vs. oral treatment). The percentage of long-term survivors (LTS) for groups receiving intracranial TMZ ranged from 25 to 37.5%; there were no LTS with oral TMZ treatment. Animals treated with radiation therapy (XRT) and intracranial TMZ (median survival not reached, LTS = 87.5%) demonstrated improved survival compared to those with intracranial TMZ alone (median survival, 41 days; LTS = 37.5%), or oral TMZ and XRT (median survival, 43 days, LTS = 38.9%).

Conclusions

The survival of tumor-bearing animals was improved with local delivery of TMZ compared with systemic administration. XRT in combination with intracranial TMZ did not cause additional toxicity and prolonged the survival even further.

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Abbreviations

TMZ:

Temozolomide

GBM:

Glioblastoma multiforme

pCPP:SA:

Poly[bis(p-carboxyphenoxy propane) sebacic acid]

References

  1. NationalComprehensive Cancer Network. Clinical Practice Guidelines in Oncology-Central Nervous System Cancers v.1.2006, 4/18/06

  2. 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; European Organisation for Research, Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group (2005) Radiotherapy plus concomitant and adjuvant TMZ for glioblastoma. N Engl J Med 352(10):987–996

    Google Scholar 

  3. Cohen MH, Johnson JR, Pazdur R (2005) Food and drug administration drug approval summary: temozolomide plus radiation therapy for the treatment of newly diagnosed glioblastoma multiforme. Cancer Res 11(19):6767–6771

    Article  CAS  Google Scholar 

  4. Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, Black K, Sisti M, Brem S, Mohr G et al (1995) Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Ploymer-Brain Tumor Treatment Group. Lancet 345:1008–1012

    Article  PubMed  CAS  Google Scholar 

  5. Westphal M, Hilt DC, Bortey E et al (2003) A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. J Neurooncol 5:79–88

    CAS  Google Scholar 

  6. Valtonen S, Timonen U, Toivanen P, Kalimo H, Kivipelto L, Heiskanen O, Unsgaard G, Kuurne T (1997) Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. Neurosurgery 41:44–48

    Article  PubMed  CAS  Google Scholar 

  7. Gallia GL, Brem S, Brem H (2005) Local treatment of malignant brain tumors using implantable chemotherapeutic polymers. J Natl Compr Canc Netw 3(5):721–728

    PubMed  Google Scholar 

  8. Newlands ES, Stevens MF, Wedge SR, Wheelhouse RT, Brock C (1997) Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev 23:35–61

    Article  PubMed  CAS  Google Scholar 

  9. Hanes J, Chiba M, Langer R (1998) Degradation of porous poly(anhydride-co-imide) microspheres and implications for controlled macromolecule delivery. Biomaterials 19(1–3):163–172

    Article  PubMed  CAS  Google Scholar 

  10. Hanes J, Sills AK, Zhao Z, Suh KW, Tyler BM, DiMeco F, Brat DJ, Choti MA, Leong KW, Pardoll DM, Brem H (2001) Controlled local delivery of interleukin-2 by biodegradable polymers protects animals from experimental brain tumors and liver tumors. Pharm Res 18(7):899–906

    Article  PubMed  CAS  Google Scholar 

  11. Hsu W, Lesniak MS, Tyler B, Brem H (2005) Local delivery of interleukin-2 and adriamycin is synergistic in the treatment of experimental malignant glioma. J Neurooncol 74(2):135–140

    Article  PubMed  CAS  Google Scholar 

  12. Tamargo RJ, Myseros JS, Epstein JI et al (1993) Interstitial chemotherapy of the 9L gliosarcoma: controlled release polymers for drug delivery in the brain. Cancer Res 53:329–333

    PubMed  CAS  Google Scholar 

  13. Brock CS, Newlands ES, Wedge SR, Bower M, Evans H, Colquhoun I, Roddie M, Glaser M, Brampton MH, Rustin GJ. (1998) Phase I trial of temozolomide using an extended continuous oral schedule. Cancer Res 58(19):4363–4348

    PubMed  CAS  Google Scholar 

  14. Tuettenberg J, Grobholz R, Korn T, Wenz F, Erber R, Vajkoczy P (2005) Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multiforme. J Cancer Res Clin Oncol. 131(1):31–40. Epub Sep 28, 2004

    Google Scholar 

  15. Wedge SR, Porteous JK, Glaser MG, Marcus K, Newlands ES (1997) In vitro evaluation of temozolomide combined with X-irradiation. Anticancer Drugs 8(1):92–97

    Article  PubMed  CAS  Google Scholar 

  16. Colvin OM, Friedman HS, Gamcsik MP, Fenselau C, Hilton J (1993) Role of glutathione in cellular resisrance to alkylating agents. Adv Enzyme Regul 33:19–26

    Article  PubMed  CAS  Google Scholar 

  17. Newlands ES, Blackledge GR, Slack JA, Rustin GJ, Smith DB, Stuart NS, Quarterman CP, Hoffman R, Stevens MF, Brampton MH et al (1992) Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer 65:287–291

    PubMed  CAS  Google Scholar 

  18. Rudek MA, Donehower RC, Statkevich P, Batra VK, Cutler DL, Baker SD (2004) Temozolomide in patients with advanced cancer: phase I and pharmacokinetic study. Pharmacotherapy 24(1):16–25

    Article  PubMed  CAS  Google Scholar 

  19. Hammond LA, Eckardt JR, Baker SD, Eckhardt SG, Dugan M, Forral K, Reidenberg P, Statkevich P, Weiss GR, Rinaldu DA, Von Hoff DD, Rowinsky EK (1999) Phase I and pharmacokinetic study of temozolomide on a daily-for-5-days schedule in patients with advanced solid malignancies. J Clin Oncol 17(8):2604–2613

    PubMed  CAS  Google Scholar 

  20. Britten CD, Rowinsky EK, Baker SD, Agarwala SS, Eckardt JR, Barrington R, Diab SG, Hammond LA, Johnson T, Villalona-Calero M, Fraass U, Statkevich P, Von Hoff DD, Eckhardt SG (1999) A Phase I and pharmacokinetic study of temozolomide and cisplatin in patients with advanced solid malignancies. Clin Cancer Res 5(7):1629–1637

    PubMed  CAS  Google Scholar 

  21. Olivi A, Grossman SA, Tatter S, Barker F, Judy K, Olsen J, Bruce J, Hilt D, Fisher J, Piantadosi S (2003) Dose escalation of carmustine in surgically implanted polymers in patients with recurrent malignant glioma: a New Approaches to Brain Tumor Therapy (NABTT) CNS consortium trial. J Clin Oncol 21(9):1845–1849

    Article  PubMed  CAS  Google Scholar 

  22. Chang SM, Parney IF, Huang W, Anderson FA Jr, Asher AL, Bernstein M, Lillehei KO, Brem H, Berger MS, Laws ER (2005) Glioma Outcomes Project Investigators. Pattern of care for adults with newly diagnosed malignant glioma. JAMA. 293(20):2469–2470; author reply 2470

    Google Scholar 

  23. Raza SM, Pradilla G, Legnani FG, Thai QA, Olivi A, Weingart JD, Brem H (2005) Local delivery of antineoplastic agents by controlled-release polymers for the treatment of malignant brain tumours. Expert Opin Biol Ther 5(4):477–494

    Article  PubMed  CAS  Google Scholar 

  24. Gururangan S, Cokgor L, Rich JN, Edwards S, Affronti ML, Quinn JA, Herndon JE II, Provenzale JM, McLendon RE, Tourt-Uhlig S, Sampson JH, Stafford-Fox V, Zaknoen S, Early M, Friedman AH, Friedman HS (2001) Phase I study of Gliadel wafers plus temozolomide in adults with recurrent supratentorial high-grade gliomas. Neuro-Oncology 4:246–250

    Google Scholar 

  25. Quinn JA, Desjardins A, Weingart J, Brem H, Dolan ME, Delaney SM, Vredenburgh J, Rich J, Friedman AH, Reardon DA, Sampson JH, Pegg AE, Moschel RC, Birch R, McLendon RE, Provenzale JM, Gururangan S, Dancey JE, Maxwell J, Tourt-Uhlig S, Herndon JE 2nd, Bigner DD, Friedman HS (2005) Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma. J Clin Oncol 23(28):7178–7187

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Alia Hdeib, Adam Fisch and Sarah Posner for their technical assistance, as well as Dr. Pamela Talalay for her editorial assistance in the preparation of this manuscript. The research presented in this article was partially funded by the National Cooperative Drug Discovery Group (UO1-CA52857) of the National Cancer Institutes of Health, Bethesda, MD.

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Authors and Affiliations

  1. Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Sarah Brem, Betty Tyler, Khan Li, Gustavo Pradilla, Justin Caplan & Henry Brem

  2. Instituto Nazionale Neurologico “C. Besta”, Milan, Italy

    Federico Legnani

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  1. Sarah Brem
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  2. Betty Tyler
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  3. Khan Li
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  4. Gustavo Pradilla
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  7. Henry Brem
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Correspondence to Henry Brem.

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Brem, S., Tyler, B., Li, K. et al. Local delivery of temozolomide by biodegradable polymers is superior to oral administration in a rodent glioma model. Cancer Chemother Pharmacol 60, 643–650 (2007). https://doi.org/10.1007/s00280-006-0407-2

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  • DOI: https://doi.org/10.1007/s00280-006-0407-2

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