Cancer Chemotherapy and Pharmacology

, Volume 35, Issue 2, pp 127–131 | Cite as

Busulfan therapy of central nervous system xenografts in athymic mice

  • Rosemary H. Aaron
  • Gertrude B. Elion
  • O. Michael Colvin
  • Michael Graham
  • Steven Keir
  • Darell D. Bigner
  • Henry S. Friedman
Original Article Busulfan, Xenografts, Brain Tumor


We evaluated the antitumor activity of busulfan against a panel of tumor cell lines and xenografts in athymic nude mice derived from childhood high-grade glioma, adult high-grade glioma, ependymoma, and medulloblastoma. Busulfan displayed similar activity against a panel of four medulloblastoma cell lines (D283 Med, Daoy, D341 Med, and D425 Med) and four corresponding sublines with laboratory-generated or clinically acquired resistance to 4-hydroperoxycyclophosphamide [D283 Med (4-HCR), Daoy (4-HCR), D341 Med (4-HCR), and D458 Med] and cross-resistance to melphalan. This is consistent with a nearly total lack of cross-resistance of busulfan to 4-hydroperoxycyclophosphamide. Busulfan was active in the therapy of all but one of the subcutaneous xenografts tested, with growth delays ranging from 14.3 days in D612 EP to 58.4 days in D528 EP. Busulfan produced statistically significant increases in the median survival of mice bearing intracranial D456 MG (66%–90%), D612 EP (18%–33%), and D528 EP (89%) xenografts. These studies suggest that busulfan may be active against medulloblastomas, highgrade gliomas, and ependymomas as well as against cyclophosphamide-resistant neoplasms.

Key words

Busulfan Xenografts Brain tumor 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Alexander P, Lett JT (1960) The biological significance of the changes produced in the deoxyribonucleic acid of cells treated with radiomimetic alkylating agents. Biochem Pharmacol 4: 34–48Google Scholar
  2. 2.
    Arduino LJ, Mellinger GT (1967) Clinical trial of busulfan (NSC-750) in advanced carcinoma of prostate. Cancer Chemother Rep 51: 295–303Google Scholar
  3. 3.
    Bedford P, Fox BW (1982) Repair of DNA interstrand crosslinks after busulphan: a possible mode of resistance. Cancer Chemother Pharmacol 8: 3–7Google Scholar
  4. 4.
    Bigner SH, Mark J, Schold SC Jr, Eng LF, Bigner DD (1985) A serially transplantable human giant cell glioblastoma that maintains a near haploid stem line. Cancer Genet Cytogenet 18: 141–148Google Scholar
  5. 5.
    Bigner SH, Friedman HS, Vogelstein B, Oakes WJ, Bigner DD (1990) Amplification of the c-myc gene in human medulloblastoma cell lines and xenografts. Cancer Res 50: 2347–2350Google Scholar
  6. 6.
    Boring CC, Squires TS, Tong T (1993) Cancer statistics, 1993. CA 43: 7–26Google Scholar
  7. 7.
    Brookes P, Lawley PD (1961) The reaction of mono- and difunctional alkylating agents with nucleic acids. Biochem J 80: 496–503Google Scholar
  8. 8.
    Bullard DE, Bigner DD (1979) The heterotransplantation of human craniopharyngiomas in athymic “nude” mice. Neurosurgery 4: 308–314Google Scholar
  9. 9.
    Dunn CDR (1974) The chemical and biological properties of busulphan (Myleran). Exp Hematol 2: 101–117Google Scholar
  10. 10.
    Dunn CDR, Elson LA (1970) The effect of a homologous series of dimethanesulphonoxy-alkanes on haemopoietic colony forming units in the rat. Chem Biol Interact 2: 273–280Google Scholar
  11. 11.
    Frei E, Teicher BA, Cucchi CA, Rosowsky A, Flatow JL, Kelley MJ, Genereux P (1988) Resistance to alkylating agents: basic studies and therapeutic implications. In: Woolley PV, Tew KD (eds) Mechanisms of drug resistance in neoplastic cells. Academic Press, San Diego, pp 69–87Google Scholar
  12. 12.
    Friedman HS, Oakes WJ (1987) The chemotherapy of posterior fossa tumors in childhood. J Neurooncol 5: 217–229Google Scholar
  13. 13.
    Friedman HS, Schold SC Jr (1993) Tumor site effects: CNS tumors. In: Teicher BA (ed) Mechanisms of drug resistance in oncology. Marcel Dekker, New York, pp 251–261Google Scholar
  14. 14.
    Friedman HS, Burger PC, Bigner SH, Trojanowski JQ, Wikstrand CJ, Halperin EC, Bigner DD (1985) Establishment and characterization of the human medulloblastoma cell line and transplantable xenograft D283. Med. J Neuropathol Exp Neurol 44: 592–605Google Scholar
  15. 15.
    Friedman HS, Colvin OM, Skapek SX, Ludeman SM, Elion GB, Schold SC Jr, Jacobsen PF, Muhlbaier LH, Bigner DD (1988) Experimental chemotherapy of human medulloblastoma cell lines and transplantable xenografts with bifunctional alkylating agents. Cancer Res 48: 4189–4195Google Scholar
  16. 16.
    Friedman HS, Burger PC, Bigner SH, Trojanowski JQ, Brodeur GM, He X, Wikstrand CJ, Kurtzberg J, Berens ME, Halperin EC, Bigner DD (1988) Phenotypic and genotypic analysis of a human medulloblastoma cell line and transplantable xenograft (D341 Med) demonstrating amplification of c-myc. Am J Pathol 130: 472–484Google Scholar
  17. 17.
    Friedman HS, Schold SC Jr, Mahaley MS Jr, Colvin OM, Oakes WJ, Vick NA, Burger PC, Bigner SH, Borowitz M, Halperin EC, Djang W, Falletta JM, DeLong R, Garvin JH, DeVivo DC, Norris D, Golembe B, Winter J, Bodziner RA, Sipahi H, Bigner DD (1989) Phase II treatment of medulloblastoma and pineoblastoma with melphalan: clinical therapy based on experimental models of human medulloblastoma. J Clin Oncol 7: 904–919Google Scholar
  18. 18.
    Friedman HS, Colvin OM, Kaufman SH, Ludeman SM, Bullock N, Bigner DD, Griffith OW (1992) Cyclophosphamide resistance in medulloblastoma. Cancer Res 52: 5373–5378Google Scholar
  19. 19.
    Friedman HS, Dolan ME, Moschel RC, Pegg AE, Felker GM, Rich J, Bigner DD, Schold SC Jr (1992) Enhancement of nitrosourea activity in medulloblastoma and glioblastoma multiforme. J Natl Cancer Inst 84: 1926–1931Google Scholar
  20. 20.
    Galton GAG (1953) Myleran in chronic myeloid leukemia: results of treatment. Lancet I: 208–213Google Scholar
  21. 21.
    Groothuis DR, Blasberg RG (1985) Rational brain tumor chemotherapy. The integration of drug and tumor. Neurol Clin 3: 801–816Google Scholar
  22. 22.
    Groothuis DR, Vriesendorp FJ, Kupfer B, Warnke PC, Lapin GD, Kuruvilla A, Vick NA, Mickael MA, Patlak CS (1991) Quantitative measurements of capillary transport in brain tumors by computed tomography. Ann Neurol 30: 581–588Google Scholar
  23. 23.
    Hassan M, Ehrsson H, Smedmyr B, Totterman T, Wallin I, Oberg G, Simonsson B (1989) Cerebrospinal fluid and plasma concentrations of busulfan during high-dose therapy. Bone Marrow Transplant 4: 113–114Google Scholar
  24. 24.
    Jacobsen PF, Jenkyn DJ, Papadimitriou JM (1985) Establishment of a human medulloblastoma cell line and its heterotransplantation into nude mice. J Neuropathol Exp Neurol 44: 472–485Google Scholar
  25. 25.
    Johnson EA, Brown BW Jr (1961) The Spearman estimator for serial dilution assays. Biometrics 17: 79–88Google Scholar
  26. 26.
    Kalifa C, Hartmann O, Demeocq F, Vassal G, Covanet D, Terrier-Lacombe MJ, Valteau D, Brugieres L, Lemer KJ (1992) High-dose busulfan and thiotepa with autologous bone marrow transplantation in childhood malignant brain tumors: a phase II study. Bone Marrow Transplant 9: 227–233Google Scholar
  27. 27.
    Livingston RB, Carter SK (1970) Busulfan. In: Livingston RB, Carter SK (eds) Single agents in cancer chemotherapy. IFI/Plenum, New York, pp 112–129Google Scholar
  28. 28.
    Lu C, Braine HG, Kaizer H, Saral R, Tutschka PJ, Santos GW (1984) Preliminary results of high-dose busulfan and cyclophosphamide with syngeneic or autologous bone marrow rescue. Cancer Treat Rep 68: 711–717Google Scholar
  29. 29.
    Mitchell MP, Walker IG (1972) Studies on the cytotoxicity of myleran and dimethyl myleran. Can J Biochem 50: 1074–1081Google Scholar
  30. 30.
    Peters WP, Henner WD, Grochow LB, Olsen G, Edwards S, Stanbuck H, Stuart A, Gockerman J, Moore J, Bast RC Jr, Seigler HF, Colvin OM (1987) Clinical and pharmacologic effects of high dose single agent busulfan with autologous bone marrow support in the treatment of solid tumors. Cancer Res 47: 6402–6406Google Scholar
  31. 31.
    Porcellini A, Talevi N, Marchetti-Rossi MT, Palazzi M, Manna A, Sparaventi G, Delfini C, Valentini M (1987) Limiting-dilution analysis for the determination of leukemic cell frequencies after bone marrow decontamination with mafosfamide or merocyanine 540. Blood 70: 1543–1549Google Scholar
  32. 32.
    Roberts JJ (1978) The repair of DNA modified by cytotoxic, mutagenic, and carcinogenic chemicals. Adv Radiat Biol 7: 211–436Google Scholar
  33. 33.
    Roberts JJ, Warwick GP (1961) The mode of action of alkylating agents. II. Studies of the metabolism of Myleran. The reaction of Myleran with some naturally occurring thiols in vitro. Biochem Pharmacol 6: 205–216Google Scholar
  34. 34.
    Roberts JJ, Warwick GP (1961) The mode of action of alkylating agents. III. The dimethanesulphonoxybutane (Myleran),S-β-L-alanyltetrahydrothiophenium mesylate, tetrahydrothiophene and tetrahydrothiophene-1:1-dioxide in the rat, rabbit and mouse. Biochem Pharmacol 6: 217–227Google Scholar
  35. 35.
    Santos GW, Tutschka PJ, Brookmeyer R, Saral R, Beschorner WE, Bias WB, Braine HG, Burns WH, Elfenbein GJ, Kaizer H, Mellits D, Sensenbrenner LL, Stuart RK, Yeager AM (1983) Marrow transplantations for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med 309: 1347–1353Google Scholar
  36. 36.
    Schold SC Jr, Brent TP, Hofe E von, Friedman HS, Mitra S, Bigner DD, Swenberg JA, Kleihues P (1989)O 6-Alkylguanine-DNA alkyltransferase sensitivity to procarbazine in human brain tumor xenografts. J Neurosurg 70: 573–577Google Scholar
  37. 37.
    Teicher BA, Cucchi CA, Lee JB, Flatow JL, Rosowsky A, Frei E III (1986) Alkylating agents: in vitro studies of cross-resistance patterns in human cell lines. Cancer Res 46: 4379–4883Google Scholar
  38. 38.
    Tong WP, Ludlum DB (1980) Crosslinking of DNA by busulfan formation of diguanyl derivatives. Biochim Biophys Acta 608: 174–181Google Scholar
  39. 39.
    Vassal G, Gouyette A, Hartmann O, Pico JL, Lemerle J (1989) Pharmacokinetics of high-dose busulfan in children. Cancer Chemother Pharmacol 24: 386–390Google Scholar
  40. 40.
    Verly WG, Brakier L (1969) The lethal action of monofunctional and bifunctional alkylating agents on T7 coliphage. Biochim Biophys Acta 174: 674–685Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Rosemary H. Aaron
    • 1
  • Gertrude B. Elion
    • 3
  • O. Michael Colvin
    • 5
  • Michael Graham
    • 1
  • Steven Keir
    • 1
  • Darell D. Bigner
    • 2
    • 4
  • Henry S. Friedman
    • 1
    • 2
    • 4
  1. 1.Department of PediatricsDuke University Medical CenterDurhamUSA
  2. 2.Department of PathologyDuke University Medical CenterDurhamUSA
  3. 3.Department of PharmacologyDuke University Medical CenterDurhamUSA
  4. 4.Preuss Laboratory for Brain Tumor ResearchDuke University Medical CenterDurhamUSA
  5. 5.The Johns Hopkins Oncology CenterThe Johns Hopkins UniversityBaltimoreUSA

Personalised recommendations