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4 Translation into Clinical Trials: Humans Are Not Large Mice

4 Translation into Clinical Trials: Humans Are Not Large Mice

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Delivery of therapeutic agents to HGGs is a difficult task that has perplexed neurosurgeons and brain tumor researchers for several decades. The effectiveness of some

chemotherapeutic agents against gliomas in vitro has been recognized for many

years, but the BBB minimizes the amount of drug that penetrates tumors when

administered systemically, even with highly lipophilic nitrosureas.124

Toxicity limits how high a systemic dose can be given and prevents satisfactory

levels of agents from reaching tumors in the brain. This circumstance led to many

attempts to treat brain tumors with intratumoral or local injections of methotrexate

or nitrosureas in the 1960s and 1970s, all with minimal beneficial responses.125–129

Despite the lack of therapeutic benefit, these early investigations were encouraging

because they found that intratumoral injections of chemotherapeutic agents resulted

in lower systemic toxicity.129,130

The revolution in molecular biology techniques and other scientific advances

are leading to a dramatic increase in discoveries of potential therapeutic agents for

the treatment of cancer. These agents include traditional chemotherapies, molecular

therapies, targeted toxins, viruses, liposomal–DNA complexes, viral packaging cells,

stem cells, and others.131–133 Although few of the new therapeutic modalities have

achieved mainstream use in cancer therapy as yet, it is likely that some will do so

soon. To allow brain tumor patients to benefit from these exciting new developments,

a method to deliver therapeutic agents to the brain in a safe and effective manner

must be developed. It is possible that this stumbling block to progress in the treatment

of HGGs will be overcome by promising developments in CED.


Traditional means of delivering agents to the brain have involved direct injection

into the parenchyma or cerebrospinal fluid. These injections rely on diffusion of the

delivered agent to reach brain tissue away from the injected site. Unfortunately,

multiple studies demonstrated that diffusion of agents in the brain is extremely

limited, particularly with high molecular weight or polar molecules.134–136

Attempts have been made to overcome this limitation with use of multiple

intraparenchymal catheters.137 One study involving cisplatin infusion via 68 catheters

still did not produce a significant impact on the patient’s prognosis. This suggests

that far too many catheters would be required to treat gliomas in this fashion. A

more feasible approach is to use fewer catheters and increase the volume of diffusion

through each catheter using CED.

CED uses sustained intracerebral infusion to induce a convective interstitial fluid

current that has the potential to homogeneously distribute even large molecules great

distances within the brain by displacing interstitial fluid.138 In animal models, CED

achieved high homogeneous concentrations of various macromolecular therapeutic

agents throughout large regions of the brain that were several orders of magnitude

greater than those obtainable by systemic delivery.139 The potential benefit of CED

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in the treatment of brain tumors in animal models has been demonstrated in several


A significant limitation to interpreting data from CED experiments comes from

the fact that human brains are much larger than those of the animal models routinely

used. Although a few studies have been conducted using CED in humans,142 no data

are available on the actual distribution of agents delivered in the human brain via

this method. Data recently submitted for publication demonstrate distribution of at

least 10% of the injected concentration of a macromolecule within a nearly spherical

radius over 4 cm from the catheter tip throughout the gray and white matter surrounding a tumor resection cavity (D. Bigner, personal communication, 2004).

In addition to this encouraging data on distribution of agents in the human brain

using CED, two clinical trials demonstrated the efficacy of CED in treating human

brain tumor patients. In a clinical trial by Laske et al., 9 of 15 malignant brain tumor

patients had greater than 50% reductions in tumor volume after receiving therapeutic

agents via CED.142 Although local toxicity was seen at the highest dose administered,

no systemic toxicity was observed, suggesting CED is an effective way to deliver

therapeutic toxins to the human brain. In a trial by Rand et al., 7 of 9 patients treated

with CED had increased tumor necrosis as evidenced by reduced gadolinium

enhancement on MRI following therapy.143 One patient survived more than 18

months after therapy.

Although these results are encouraging, several limiting factors remain as obstacles to the use of CED in the treatment of HGG patients. First, although a distribution

of agent 4 cm from the catheter tip is encouraging, the technique still requires

infusion via multiple catheters and careful optimization and planning to deliver

therapeutic agent to the region surrounding a tumor or its resection cavity. Second,

tumors clearly alter the fluid dynamics in the brain and the effect of this alteration

on CED is poorly understood. Despite these limitations, further studies aimed at

optimizing catheter design and infusion parameters should identify modifications

capable of effectively addressing these issues now that the potential utility of this

approach has been established in humans.


Although CED could be used to deliver any of a number of therapeutic agents to

treat brain tumors, the majority of work to date has utilized targeted toxins. A

targeted toxin is attached to a receptor ligand; an immunotoxin consists of a toxin

attached to an antibody that recognizes a receptor. In both cases, receptors selected

for targeting are over-expressed on tumor cells (for simplicity, this chapter will

use the term “targeted toxin” in reference to both moieties). Targeted toxins allow

targeted delivery of potent toxins to tumors with relative sparing of normal tissue.133 The specificity of these agents is enhanced and systemic toxicity reduced

by delivery to an anatomically isolated compartment, such as the intracranial or

intrathecal space.144

Bacterial and plant toxins are potent cytotoxic agents that have been exploited

in targeted toxin therapy. Such toxins have at least two important advantages over

most chemotherapeutic agents: (1) they are far more potent, while most

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chemotherapies require >104 molecules to kill a single tumor cell, many toxins

require only one,133 and (2) they are active against hypoxic and nondividing cells,

making them potentially effective against tumors that are resistant to chemotherapy

and radiation.145

The powerful potential of targeted toxins derives from a combination of the high

potency and toxicity of the toxin with the highly selective binding of a receptor

ligand or antibody. Critical to the success of targeted toxin therapy is the identification of a receptor that is ubiquitously highly expressed on the tumor but not on

surrounding tissue. This has been accomplished in tumors outside the CNS. Clinical

trials using targeted toxin therapy have targeted interleukin-2 receptors in hematologic malignancies146 and interleukin-13 receptors in squamous cell carcinomas.147

Other trials have used tumor-specific antibodies to target ovarian, breast, and colon


In order for targeted toxin therapy to be effective against HGGs, a receptor that

is commonly over-expressed on the tumors must be identified and targeted. It has

been known for several years that HGGs frequently over-express EGFR.150 Overexpression is often associated with amplification of the EGFR gene. A simultaneous

examination of GBM samples for EGFR gene amplification, mRNA, and protein

found approximately one-third had gene amplification, all had mRNA, and 85% had

detectable EGFR protein151 (McLendon et al., personal communication, 2004). By

contrast, EGFR was found in only very low levels in surrounding brain — a circumstance that lends it to targeted toxin treatment with minimal unwanted toxicity.152

EGFR has two natural ligands, epidermal growth factor and transforming growth

factor alpha (TGF-α). A targeted toxin for the EGFR was designated TP-38. It is a

recombinant chimeric protein composed of TGF-α and a genetically engineered

form of the pseudomonas exotoxin PE-38. Encouraging results of a Phase I clinical

trial examining treatment of patients with recurrent HGGs using CED of TP-38 have

recently been submitted for publication.153

Other receptors over-expressed on HGGs have been identified. Targeted toxins

for interleukin-4 and interleukin-13 receptors showed therapeutic efficacy against

HGGs.154,155 Further work using sophisticated molecular biology techniques will

undoubtedly identify other potential receptors for toxin targeting and enhance the

potential of this novel therapy for HGG patients.


The relatively recent revolution in molecular biology techniques has in fact led to

many significant discoveries of underlying mechanisms of the development of

HGGs, only a few of which were covered here. Even more importantly, a variety

of scientific advances led to the development and rapid translation to clinical trials

of many novel forms of cancer therapy, broadly increasing the landscape of

potential therapies far beyond the traditional modes of surgery, chemotherapy, and


Although we have not yet discovered the combination of novel therapy and better

understanding of underlying tumor mechanisms that will lead to an efficacious new

© 2005 by CRC Press LLC

treatment of HGGs, many promising new therapies are on the horizon. In this

environment of rapid new discovery, it remains of utmost importance that neurosurgeons are involved in and informed of the development of these exciting new

therapies that may soon allow us to better serve our sickest patients.


1. Central Brain Tumor Registry of the U.S., Primary Brain Tumors in the United States,

Statistical Report, 1995-1999 and Statistical Report, 2002-2003, Chicago.

2. Laws, E.R., Parney, I.F., Huang, W. et al., Survival following surgery and prognostic

factors for recently diagnosed malignant glioma: data from the Glioma Outcomes

Project, J. Neurosurg., 2003, 99(3), 467–473.

3. Lacroix, M., Abi-Said, D., Fourney, D.R. et al., A multivariate analysis of 416 patients

with glioblastoma multiforme: prognosis, extent of resection, and survival [comment],

J. Neurosurg., 2001, 95(2), 190–198.

4. Gururangan, S. and Friedman, H.S., Innovations in design and delivery of chemotherapy for brain tumors, Neuroimaging Clin. N. Amer., 2002, 12(4), 583–597.

5. Dunkel, I.J. and Finlay, J.L., High-dose chemotherapy with autologous stem cell

rescue for brain tumors, Crit. Rev. Oncol. Hematol., 2002, 41(2), 197–204.

6. Ciordia, R., Supko, J., Gatineau, M. et al., Cytotoxic chemotherapy, advances in

delivery, pharmacology, and testing, Curr. Oncol. Rep., 2000, 2(5), 445–453.

7. Fathallah-Shaykh, H., New molecular strategies to cure brain tumors, Arch. Neurol.,

1999, 56(4), 449–453.

8. Karpati, G., Li, H., and Nalbantoglu, J., Molecular therapy for glioblastoma, Curr.

Opin. Molecular Therap., 1999, 1(5), 545–552.

9. Soling, A. and Rainov, N.G., Dendritic cell therapy of primary brain tumors, Molecular Med., 2001, 7(10), 659–667.

10. Fecci, P.E. and Sampson, J.H., Clinical immunotherapy for brain tumors, Neuroimaging Clin. N. Amer., 2002, 12(4), 641–664.

11. Virasch, N. and Kruse, C.A., Strategies using the immune system for therapy of brain

tumors, Hematol. Oncol. Clin. N. Amer., 2001, 15(6), 1053–1071.

12. Rapoport, S.I., Advances in osmotic opening of the blood–brain barrier to enhance

CNS chemotherapy, Expert Opin. Invest. Drugs, 2001, 10(10), 1809–1818.

13. van Vulpen, M., Kal, H.B., Taphoorn, M.J. et al., Changes in blood–brain barrier

permeability induced by radiotherapy: implications for timing of chemotherapy

(review), Oncol. Rep., 2002, 9(4), 683–688.

14. Alexander, E., III, Optimizing brain tumor resection: midfield interventional MR

imaging, Neuroimaging Clin. N. Amer., 2001, 11(4), 659–672.

15. Metzger, A.K. and Lewin, J.S., Optimizing brain tumor resection: low field interventional MR imaging, Neuroimaging Clin. N. Amer., 2001, 11(4), 651–657.

16. Tummala, R.P., Chu, R.M., Liu, H. et al., Optimizing brain tumor resection: high

field interventional MR imaging, Neuroimaging Clin. N. Amer., 2001, 11(4), 673–683.

17. Oldfield, E.H., Ram, Z., Culver, K.W. et al., Gene therapy for the treatment of brain

tumors using intra-tumoral transduction with the thymidine kinase gene and intravenous gancyclovir, Human Gene Therap., 1993, 4(1), 39–69.

© 2005 by CRC Press LLC

18. Takamiya, Y., Short, M.P., Ezzeddine, Z.D. et al., Gene therapy of malignant brain

tumors: a rat glioma line bearing the herpes simplex virus type 1-thymidine kinase

gene and wild type retrovirus kills other tumor cells, J. Neurosci. Res., 1992, 33(3),


19. Martuza, R.L., Malick, A., Markert, J.M. et al., Experimental therapy of human

glioma by means of a genetically engineered virus mutant, Science, 1991, 252(5007),


20. Varghese, S. and Rabkin, S.D., Oncolytic herpes simplex virus vectors for cancer

virotherapy, Canc. Gene Ther., 2002, 9, 967–978.

21. Kaplitt, M., Tjuvajev, J., Leib, D.A. et al., Mutant herpes simplex virus-induced

regression of tumors growing in immunocompetent rats, J. Neurol. Oncol., 1994, 19,


22. Mineta, T., Rabkin, S.D., and Martuza, R.L. Treatment of malignant gliomas using

ganciclovir-hypersensitive, ribonucleotide reductase-deficient herpes simplex viral

mutant, Cancer Res., 1994, 54(15), 3963–3966.

23. Chambers, R., Gillespie, G.Y., Soroceanu, L. et al., Comparison of genetically engineered herpes simplex viruses for the treatment of brain tumors in a SCID mouse

model of human malignant glioma, PNAS, 1995, 92(5), 1411–1415.

24. Chou, J., Kern, E.R., Whitley, R.J. et al., Mapping of herpes simplex virus-1 neurovirulence to gamma 134.5: a gene nonessential for growth in culture, Science, 1990,

250(4985), 1262–1266.

25. Mineta, T., Rabkin, S.D., Yazaki, T. et al., Attenuated multi-mutated herpes simplex

virus-1 for the treatment of malignant gliomas, Nature Med., 1995, 1(9), 938–943.

26. Goldstein, D.J. and Weller, S.K., Herpes simplex virus type 1-induced ribonucleotide

reductase activity is dispensable for virus growth and DNA synthesis, isolation and

characterization of an ICP6 lacZ insertion mutant, J. Virol., 1988, 62(1), 196–205.

27. Goldstein, D.J. and Weller, S.K. Factor(s) present in herpes simplex virus type 1infected cells can compensate for the loss of the large subunit of the viral ribonucleotide reductase: characterization of an ICP6 deletion mutant, Virology, 1988, 166(1),


28. Jacobson, J.G., Leib, D.A., Goldstein, D.J. et al., A herpes simplex virus ribonucleotide reductase deletion mutant is defective for productive acute and reactivatable

latent infections of mice and for replication in mouse cells, Virology, 1989, 173(1),


29. Coen, D.M., Goldstein, D.J., and Weller, S.K. Herpes simplex virus ribonucleotide

reductase mutants are hypersensitive to acyclovir, Antimicrob. Agents Chemother.,

1989, 33(8), 1396–1399. Erratum in Antimicrob. Agents Chemother., 1989


30. Hunter, W.D., Martuza, R.L., Feigenbaum, F. et al., Attenuated, replication-competent

herpes simplex virus type 1 mutant G207: safety evaluation of intracerebral injection

in non-human primates, J. Virol., 1999, 73, 6319–6326.

31. Markert, J.M., Medlock, M.D., Rabkin, S.D. et al., Conditionally replicating herpes

simplex virus mutant G207 for the treatment of malignant glioma: results of a phase

I trial [comment], Gene Ther., 2000, 7(10), 867–874.

32. Rampling, R., Cruickshank, G., Papanastassiou, V. et al., Toxicity evaluation of

replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients

with recurrent malignant glioma [comment], Gene Ther., 2000, 7(10), 859–866.

33. Toda, M., Rabkin, S.D., Kojima, H. et al., Herpes simplex virus as an in situ cancer

vaccine for the induction of specific anti-tumor immunity, Hum. Gene Ther. 1999,

10, 385–393.

© 2005 by CRC Press LLC

34. Miyatake, S., Iyer, A., Martuza, R.L. et al., Transcriptional targeting of herpes simplex

virus for cell-specific replication, J. Virol., 1997, 71, 5124–5132.

35. Chung, R.Y., Saeki, Y., and Chiocca, E.A., B-myb promoter retargeting of herpes

simplex virus gamma 34.5 gene-mediated virulence toward tumor and cycling cells,

J. Virol., 1999, 73, 7556–7564.

36. Yamamura, H., Hadhio, M., Noguchi, M. et al., Identification of transcriptional

regulatory sequences of human calponin promoter and their use in targeting a conditionally replicating herpes vector to malignant human soft tissue and bone tumors,

Cancer Res., 2001, 61, 3969–3977.

37. Alemany, R., Gomez-Manzano, C., Balague, C. et al., Gene therapy for gliomas:

molecular targets, adenoviral vectors, and oncolytic adenoviruses, Exp. Cell Res.,

1999, 252(1), 1–12.

38. Rodriguez, R., Schuur, E.R., Lim, H.Y. et al., Prostate attenuated replication competent adenovirus (ARCA)CN706: a selective cytotoxic for prostate-specific antigenpositive prostate cancer cells, Cancer Res., 1997, 57, 2559–2563.

39. Alemany, R., Balague, C., and Curiel, D.T., Replicative adenoviruses for cancer

therapy, Nature Biotech., 2000, 18, 723–727.

40. Chen, S.H., Shine, H.D., Goodman, J.C. et al., Gene therapy for brain tumors:

regression of experimental gliomas by adenovirus-mediated gene transfer in vivo,

PNAS,1994, 91(8), 3054–3057.

41. Adachi, Y., Tamiya, T., Ichikawa, T. et al., Experimental gene therapy for brain tumors

using adenovirus-mediated transfer of cytosine deaminase gene and uracil phosphoribosyltransferase gene with 5-fluorocytosine, Hum. Gene Ther., 2000, 11(1), 77–89.

42. Dewey, R.A., Morrissey, G., Cowsill, C.M. et al., Chronic brain inflammation and

persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy: implications for clinical

trials, Nature Med.,1999, 5(11), 1256–1263.

43. Yang, Y., Li, Q., Ertl, H.C. et al., Cellular and humoral immune responses to viral

antigens create barriers to lung-directed gene therapy with recombinant adenoviruses,

J. Virol., 1995, 69, 2004–2015.

44. Hollon, T., Researchers and regulators reflect on first gene therapy death, Nature

Med., 2000, 6(1), 6.

45. Smith, R.R., Huebner, R.J., Rowe, W.P. et al., Studies on the use of viruses in the

treatment of carcinoma of the cervix, Cancer, 1956, 9, 1211–1218.

46. Bischoff, J.R., Kirn, D.H., Williams, A. et al., An adenovirus mutant that replicates

selectively in p53-deficient human tumor cells [comment], Science, 1996, 274(5286),


47. Rothmann, T., Hengstermann, A., Whitaker, N.J. et al., Replication of ONYX-015,

a potential anticancer adenovirus, is independent of p53 status in tumor cells, J. Virol.,

1998, 72(12), 9470–9478.

48. Dix, B.R., Edwards, S.J., and Braithwaite, A.W., Does the antitumor adenovirus

ONYX-015/dl1520 selectively target cells defective in the p53 pathway? J. Virol.,

2001, 75(12), 5443–5447.

49. Geoerger, B., Grill, J., Opolon, P. et al., Oncolytic activity of the E1B-55 kDa-deleted

adenovirus ONYX-015 is independent of cellular p53 status in human malignant

glioma xenografts, Cancer Res., 2002, 62(3), 764–772.

50. Ganly, I., Kirn, D., Eckhardt, G. et al., A phase I study of Onyx-015, an E1B attenuated

adenovirus administered intratumorally to patients with recurrent head and neck

cancer, Clin. Cancer Res., 2000, 6(3), 798–806. Erratum to correct author’s name in

Clin. Cancer Res., 2000 6(5), 2120.

© 2005 by CRC Press LLC

51. Fueyo, J., Gomez-Manzano, C., Alemany, R. et al., A mutant oncolytic adenovirus

targeting the Rb pathway produces anti-glioma effect in vivo, Oncogene, 2000, 19(1),

2–21. Erratum in Oncogene, 2000, 19(43), 5038.

52. Yu, D.C., Sakamoto, G.T., and Henderson, D.R., Identification of the transcriptional

regulatory sequences of human kallikrein 2 and their use in the construction of calydon

virus 764: an attenuated replication competent adenovirus for prostate cancer therapy,

Cancer Res., 1999, 59(7), 1498–1504.

53. Hallenbeck, P.L., Chang, Y.N., Hay, C. et al., A novel tumor-specific replicationrestricted adenoviral vector for gene therapy of hepatocellular carcinoma, Hum. Gene

Ther., 1999, 10(10), 1721–1733.

54. Stojdl, D.F., Lichty, B., Knowles, S. et al., Exploiting tumor-specific defects in the

interferon pathway with a previously unknown oncolytic virus, Nature Med., 2000,

6, 821–825.

55. Coffey, M.C., Strong, J.E., Forsyth, P.A. et al., Reovirus therapy of tumors with

activated Ras pathway, Science, 1998, 282, 1332–1334.

56. Gromeier, M., Lachmann, S., Rosenfeld, M.R. et al., Intergeneric poliovirus recombinants for the treatment of malignant glioma [comment], PNAS, 2000, 97(12),


57. Gromeier, M., Alexander, L., and Wimmer, E., Internal ribosomal entry site substitution eliminates neurovirulence in intergeneric poliovirus recombinants, PNAS, 1996,

93(6), 2370–2375.

58. Gromeier, M., Bossert, B., Arita, M. et al., Dual stem loops within the poliovirus

internal ribosomal entry site control neurovirulence, J. Virol. 1999, 73(2), 958–964.

59. Wickham, T.J., Targeting adenovirus, Gene Ther., 2000, 7, 110–114.

60. Yoshida, Y., Sadata, A., Zhang, W. et al., Generation of fiber-mutant recombinant

adenoviruses for gene therapy of malignant glioma, Hum. Gene Ther., 1998, 9(17),


61. Freytag, S.O., Rogulski, K.R., Paielli, D.L. et al., A novel three-pronged approach

to kill cancer cells selectively: concomitant viral, double suicide gene, and radiotherapy [comment], Hum. Gene Ther., 1998, 9(9), 1323–1333.

62. Toda, M., Martuza, R.L., Kojima, H. et al., In situ cancer vaccination: an IL-12

defective vector/replication-competent herpes simplex virus combination induces

local and systemic antitumor activity, J. Immunol., 1998, 160(9), 4457–4464.

63. Todo, T., Martuza, R.L., Dallman, M.J. et al., In situ expression of soluble B7-1 in

the context of oncolytic herpes simplex virus induces potent antitumor immunity,

Cancer Res., 2001, 61(1), 153–161.

64. Carew, J.F., Kooby, D.A., Halterman, M.W. et al., A novel approach to cancer therapy

using an oncolytic herpes virus to package amplicons containing cytokine genes,

Molecular Ther., 2001, 4(3), 250–256.

65. Walker, J.R., McGeagh, K.G., Sundaresan, P. et al., Local and systemic therapy of

human prostate adenocarcinoma with the conditionally replicating herpes simplex

virus vector G207, Hum. Gene Ther., 1999, 10(13), 2237–2243.

66. Wong, R.J., Joe, J.K., Kim, S.H. et al., Oncolytic herpes virus effectively treats murine

squamous cell carcinoma and spreads by natural lymphatics to treat sites of lymphatic

metastases, Hum. Gene Ther., 2002, 13(10), 1213–1223.

67. Coukos, G., Makrigiannakis, A., Montas, S. et al., Multi-attenuated herpes simplex

virus-1 mutant G207 exerts cytotoxicity against epithelial ovarian cancer but not

normal mesothelium and is suitable for intraperitoneal oncolytic therapy, Cancer

Gene Ther., 2000, 7(2), 275–283.

© 2005 by CRC Press LLC

68. Ikeda, K., Ichikawa, T., Wakimoto, H. et al., Oncolytic virus therapy of multiple

tumors in the brain requires suppression of innate and elicited antiviral responses,

Nature Med., 1999, 5(8), 881–887.

69. Chillon, M., Lee, J.H., Fasbender, A. et al., Adenovirus complexed with polyethylene

glycol and cationic lipid is shielded from neutralizing antibodies in vitro, Gene Ther.,

1998, 5(7), 995–1002.

70. Coukos, G., Makrigiannakis, A., Kang, E.H. et al., Use of carrier cells to deliver a

replication-selective herpes simplex virus-1 mutant for the intraperitoneal therapy of

epithelial ovarian cancer, Clin. Cancer Res., 1999, 5(6), 1523–1537.

71. Ekstrand, A.J., Sugawa, N., James, C.D. et al., Amplified and rearranged epidermal

growth factor receptor genes in human glioblastomas reveal deletions of sequences

encoding portions of the N- and/or C-terminal tails, PNAS, 1992, 89(10), 4309–4913.

72. Shapiro, J.R., Genetics of nervous system tumors. Hematol. Oncol. Clin. N. Amer.,

2001, 15(6), 961–977.

73. Lal, A., Glazer, C.A., Martinson, H.M. et al., Mutant epidermal growth factor receptor

up-regulates molecular effectors of tumor invasion, Cancer Res., 2002, 62(12),


74. Lang, F.F., Miller, D.C., Koslow, M. et al., Pathways leading to glioblastoma multiforme: a molecular analysis of genetic alterations in 65 astrocytic tumors, J. Neurosurg., 1994, 81(3), 427–436.

75. Lang, F.F., Yung, W.K., Sawaya, R. et al., Adenovirus-mediated p53 gene therapy

for human gliomas, Neurosurgery, 1999, 45(5), 1093–1094.

76. Broaddus, W.C., Liu, Y., Steele, L.L. et al., Enhanced radiosensitivity of malignant

glioma cells after adenoviral p53 transduction, J. Neurosurg., 1999, 91(6), 997–1004.

77. Saleh, M., Stacker, S.A., and Wilks, A.F., Inhibition of growth of C6 glioma cells in

vivo by expression of antisense vascular endothelial growth factor sequence, Cancer

Res., 1996, 56(2), 393–401.

78. Zlokovic, B.V. and Apuzzo, M.L., Cellular and molecular neurosurgery: pathways

from concept to reality: part II: vector systems and delivery methodologies for gene

therapy of the central nervous system, Neurosurgery, 1997, 40(4), 805–813.

79. Weller, M., Malipiero, U., Rensing-Ehl, A. et al., Fas/APO-1 gene transfer for human

malignant glioma, Cancer Res., 1995, 55(13), 2936–2944.

80. Kondo, S., Ishizaka, Y., Okada, T. et al., FADD gene therapy for malignant gliomas

in vitro and in vivo [comment], Hum. Gene Ther., 1998, 9(11), 1599–1608.

81. Shinoura, N., Yoshida, Y., Asai, A. et al., Adenovirus-mediated transfer of p53 and

Fas ligand drastically enhances apoptosis in gliomas, Cancer Gene Ther., 2000, 7(5),


82. Shinoura, N., Koike, H., Furitu, T. et al., Adenovirus-mediated transfer of caspase-8

augments cell death in gliomas: implication for gene therapy, Hum. Gene Ther., 2000,

11(8), 1123–1137.

83. Fecci, P.E., Gromeier, M., and Sampson, J.H., Viruses in the treatment of brain tumors,

Neuroimaging Clin. N. Amer., 2002, 12(4), 553–570.

84. Polyak, K. and Riggins, G.J., Gene discovery using the serial analysis of gene

expression technique, implications for cancer research, J. Clin. Oncol., 2001, 19(11),


85. Eck, S.L., Alavi, J.B., Alavi, A. et al., Treatment of advanced CNS malignancies with

the recombinant adenovirus H5.010RSVTK: a phase I trial, Hum. Gene Ther., 1996,

7(12), 1465–1482.

86. van Dillen, I.J., Mulder, N.H., Vaalburg, W. et al., Influence of the bystander effect

on HSV-tk/GCV gene therapy: a review, Curr. Gene Ther., 2002, 2(3), 307–322.

© 2005 by CRC Press LLC

87. Hacein-Bey-Abina, S., von Kalle, C., Schmidt, M. et al., A serious adverse event

after successful gene therapy for X-linked severe combined immunodeficiency [comment], New Eng. J. Med., 2003, 348(3), 255–256.

88. Culver, K.W., Ram, Z., Wallbridge, S. et al., In vivo gene transfer with retroviral

vector–producer cells for treatment of experimental brain tumors [comment], Science,

1992, 256(5063), 1550–1552.

89. St George, J.A., Gene therapy progress and prospects: adenoviral vectors, Gene Ther.,

2003, 10(14), 1135–1141.

90. Liu, Q. and Muruve, D.A., Molecular basis of the inflammatory response to adenovirus vectors, Gene Ther., 2003, 10(11), 935–940.

91. Lowenstein, P.R. and Castro, M.G., Inflammation and adaptive immune responses to

adenoviral vectors injected into the brain: peculiarities, mechanisms, and consequences, Gene Ther., 2003, 10(11), 946–954.

92. Sandmair, A.M., Loimas, S., Puranen, P. et al., Thymidine kinase gene therapy for

human malignant glioma using replication-deficient retroviruses or adenoviruses,

Hum. Gene Ther., 2000, 11(16), 2197–2205.

93. Shih, M.F., Arsenakis, M., Tiollais, P. et al., Expression of hepatitis B virus S gene

by herpes simplex virus type 1 vectors carrying alpha- and beta-regulated gene

chimeras, PNAS, 1984, 81(18), 5867–5870.

94. Chiocca, E.A., Choi, B.B., Cai, W.Z. et al., Transfer and expression of the lacZ gene

in rat brain neurons mediated by herpes simplex virus mutants, New Biol., 1990, 2(8),


95. Dobson, A.T., Margolis, T.P., Sedarati, F. et al., A latent, nonpathogenic HSV-1derived vector stably expresses beta-galactosidase in mouse neurons, Neuron, 1990,

5(3), 353–360.

96. Glorioso, J.C. and Fink, D.J., Use of HSV vectors to modify the nervous system,

Curr. Opin. Drug Discovery Dev., 2002, 5(2), 289–295.

97. Spaete, R.R. and Frenkel, N., The herpes simplex virus amplicon: a new eucaryotic

defective virus cloning–amplifying vector, Cell, 1982, 30(1), 295–304.

98. Geller, A.I. and Breakefield, X.O., A defective HSV-1 vector expresses Escherichia

coli beta-galactosidase in cultured peripheral neurons, Science, 1988, 241(4873),


99. New, K.C., Martuza, R.L., and Rabkin, S.D. Defective herpes simplex virus vectors

for the study of promoter and gene function in the CNS, Gene Ther., 1994, 1 (Suppl.

1), S79.

100. New, K.C., Gale, K., Martuza, R.L. et al., Novel synthesis and release of GABA in

cerebellar granule cell cultures after infection with defective herpes simplex virus

vectors expressing glutamic acid decarboxylase, Mol. Brain Res.,1998, 61(1–2),


101. During, M.J., Naegele, J.R., O’Malley, K.L. et al., Long-term behavioral recovery in

parkinsonian rats by an HSV vector expressing tyrosine hydroxylase [comment],

Science, 1994, 266(5189), 1399–1403.

102. Aghi, M. and Chiocca, E.A., Genetically engineered herpes simplex viral vectors in

the treatment of brain tumors: a review, Cancer Invest., 2003, 21(2), 278–292.

103. Burton, E.A., Fink, D.J., and Glorioso, J.C., Gene delivery using herpes simplex virus

vectors, DNA Cell Biol., 2002, 21(12), 915–936.

104. Miyatake, S., Martuza, R.L., and Rabkin, S.D., Defective herpes simplex virus vectors

expressing thymidine kinase for the treatment of malignant glioma, Cancer Gene

Ther., 1997, 4(4), 222–228.

© 2005 by CRC Press LLC

105. Hoshi, M., Harada, A., Kawase, T. et al., Antitumoral effects of defective herpes

simplex virus-mediated transfer of tissue inhibitor of metalloproteinases-2 gene in

malignant glioma U87 in vitro: consequences for anti-cancer gene therapy, Cancer

Gene Ther., 2000, 7(5), 799–805.

106. Kanno, H., Hattori, S., Sato, H. et al., Experimental gene therapy against subcutaneously implanted glioma with a herpes simplex virus-defective vector expressing

interferon-gamma, Cancer Gene Ther., 1999, 6(2), 147–154.

107. Yoshida, J., Mizuno, M., Nakahara, N. et al., Antitumor effect of an adeno-associated

virus vector containing the human interferon-beta gene on experimental intracranial

human glioma, Japn. J. Cancer Res., 2002, 93(2), 223–228.

108. Mizuno, M., Yoshida, J., Colosi, P. et al., Adeno-associated virus vector containing

the herpes simplex virus thymidine kinase gene causes complete regression of intracerebrally implanted human gliomas in mice in conjunction with ganciclovir administration, Japn. J. Cancer Res., 1998, 89(1), 76-80.

109. Naldini, L., Blomer, U., Gallay, P. et al., In vivo gene delivery and stable transduction

of nondividing cells by a lentiviral vector [comment], Science, 1996, 272(5259),


110. Russell, D.W. and Miller, A.D., Foamy virus vectors, J. Virol., 1996, 70, 217-222.

111. Okada, H., Okamoto, S., and Yoshida, J. Gene therapy for brain tumors: cytokine

gene therapy using DNA/liposome (series 3), No Shinkei Geka, 1994, 22(11),


112. Aoki, K., Yoshida, T., Matsumoto, N. et al., Gene therapy for peritoneal dissemination

of pancreatic cancer by liposome-mediated transfer of herpes simplex virus thymidine

kinase gene, Hum. Gene Ther., 1997, 8(9), 1105–1113.

113. Yagi, K., Ohishi, N., Hamada, A. et al., Basic study on gene therapy of human

malignant glioma by use of the cationic multilamellar liposome-entrapped human

interferon beta gene, Hum. Gene Ther., 1999, 10(12), 1975–1982.

114. Crystal, R.G., Transfer of genes to humans: early lessons and obstacles to success,

Science, 1995, 270(5235), 404–410.

115. Zhang, Y., Jeong Lee, H., Boado, R.J. et al., Receptor-mediated delivery of an

antisense gene to human brain cancer cells, J. Gene Med., 2002, 4(2), 183–194.

116. Yung, W.K., New approaches in brain tumor therapy using gene transfer and antisense

oligonucleotides, Curr. Opin. Oncol.,1994, 6(3), 235–239.

117. Carter, B.S., Zervas, N.T., and Chiocca, E.A., Neurogenetic surgery: current limitations and the promise of gene- and virus-based therapies, Clin. Neurosurg., 1999, 45,


118. Lang, F.F., Bruner, J.M., Fuller, G.N. et al., Phase I trial of adenovirus-mediated p53

gene therapy for recurrent glioma: biological and clinical results, J. Clin. Oncol.,

2003, 21(13), 2508–2518.

119. Trask, T.W., Trask, R.P., Aguilar-Cordova, E. et al., Phase I study of adenoviral

delivery of the HSV-tk gene and ganciclovir administration in patients with current

malignant brain tumors, J. Am. Soc. Gene Ther., 2000, 1(2), 195–203.

120. Shand, N., Weber, F., Mariani, L. et al., A phase 1–2 clinical trial of gene therapy

for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex

thymidine kinase gene followed by ganciclovir GLI328: European-Canadian Study

Group, Hum. Gene Ther., 1999, 10(14), 2325–2335.

121. Klatzmann, D., Valery, C.A., Bensimon, G. et al., A phase I/II study of herpes simplex

virus type 1 thymidine kinase "suicide" gene therapy for recurrent glioblastoma: Study

Group on Gene Therapy for Glioblastoma, Hum. Gene Ther., 1998, 9(17), 2595–2604.

© 2005 by CRC Press LLC

122. Ram, Z., Culver, K.W., Oshiro, E.M. et al., Therapy of malignant brain tumors by

intratumoral implantation of retroviral vector-producing cells [comment], Nature

Med., 1997, 3(12), 1354–1361.

123. Rainov, N.G., A phase III clinical evaluation of herpes simplex virus type 1 thymidine

kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation

in adults with previously untreated glioblastoma multiforme, Hum. Gene Ther., 2000,

11(17), 2389–2401.

124. Rosenblum, M.L., Wheeler, K.T., Wilson, C.B. et al., In vitro evaluation of in vivo

brain tumor chemotherapy with 1,3-bis(2-chloroethyl)-1-nitrosourea, Cancer Res.,

1975, 35(6), 1387–1391.

125. Tator, C.H. and Wassenaar, W., Intraneoplastic injection of methotrexate for experimental brain-tumor chemotherapy, J. Neurosurg., 1977, 46(2), 165–174.

126. Dommasch, D., Przuntek, H., Gruninger, W. et al., Intrathecal cytostatic chemotherapy

of meningitis carcinomatosa: clinical manifestation and cerebrospinal fluid cytology

in a case of metastatic carcinoma of the breast, Eur. Neurol., 1976, 14(3), 178–191.

127. Garfield, J., Dayan, A.D., and Weller, R.O. Postoperative intracavitary chemotherapy

of malignant supratentorial astrocytomas using BCNU. Clinical Oncology. 1975, 1(3),


128. Garfield, J. and Dayan, A.D., Postoperative intracavitary chemotherapy of malignant

gliomas: a preliminary study using methotrexate, J. Neurosurg., 1973, 39(3), 315–322.

129. Tator, C.H., Intraneoplastic injection of CCNU for experimental brain tumor chemotherapy, Surg. Neurol., 1977, 7(2), 73–77.

130. Tator, C.H., Day, A., Ng, R. et al., Chemotherapy of an experimental glioma with

nitrosoureas, Cancer Res., 1977, 37(2), 476–481.

131. Zovickian, J., Johnson, V.G., and Youle, R.J., Potent and specific killing of human

malignant brain tumor cells by an anti-transferrin receptor antibody: ricin immunotoxin, J. Neurosurg., 1987, 66(6), 850–861.

132. Jain, R.K., Delivery of novel therapeutic agents in tumors, physiological barriers and

strategies, J. Natl. Cancer Inst., 1989, 81(8), 570–576.

133. Hall, W.A., Immunotoxin treatment of brain tumors, Methods Mol. Biol., 2001, 166,


134. Oldendorf, W.H., Lipid solubility and drug penetration of the blood-brain barrier,

Proc. Soc. Exp. Biol. Med., 1974, 147(3), 813–815.

135. Hicks, J.T., Albrecht, P., and Rapoport, S.I., Entry of neutralizing antibody to measles

into brain and cerebrospinal fluid of immunized monkeys after osmotic opening of

the blood–brain barrier, Exp. Neurol., 1976, 53(3), 768–779.

136. Blasberg, R.G., Patlak, C., and Fenstermacher, J.D., Intrathecal chemotherapy: brain

tissue profiles after ventriculo-cisternal perfusion, J. Pharmacol. Exp. Ther., 1975,

195, 73–83.

137. Bouvier, G., Penn, R.D., Kroin, J.S. et al., Direct delivery of medication into a brain

tumor through multiple chronically implanted catheters, Neurosurgery, 1987, 20(2),


138. Morrison, P.F., Laske, D.W., Bobo, R.H. et al., High-flow microinfusion, tissue

penetration and pharmacodynamics, Am. J. Physiol., 1994, 266, R292–R305.

139. Bobo, R.H., Laske, D.W., Akbasak, A. et al., Convection-enhanced delivery of macromolecules in the brain, PNAS, 1994, 91(6), 2076–2080.

140. Heimberger, A.B., Archer, G.E., McLendon, R.E. et al., Temozolomide delivered by

intracerebral microinfusion is safe and efficacious against malignant gliomas in rats,

Clin. Cancer Res., 2000, 6(10), 4148–4153.

© 2005 by CRC Press LLC

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