
<b>P-glycoprotein expression in brain tumors. </b> Henson JW, Cordon-Cardo C, Posner JB. Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY. 

Overexpression of P-glycoprotein (P-gp) in cancer cells can result in resistance to several chemotherapy agents (multidrug resistance) including doxorubicin and vincristine. The drugs to which resistance develops also penetrate the blood brain barrier poorly. P-gp expression in brain capillary endothelial cells suggests that P-gp may restrict drug entry into brain tumors and thus be another mechanism of drug resistance. ,,,. P-gp expression was observed in tumor cells of two glioblastomas and a meningeal sarcoma but not in low-grade primary or metastatic tumors. In low-grade primary tumors, P-gp was present in all vascular endothelial cells. In the vascular endothelial cells of anaplastic primary brain tumors and brain metastases, P-gp expression was heterogeneous or absent. These findings are consistent with a role for P-gp in the resistance of some brain tumors to chemotherapy agents. [NOTE: there has recently been developed oral P-gp treatment for tumors, entering trials, hopefully to deal with chemotherapy drug resistance. Ed.] 
&&url PMID: 1361524 


<b>Therapeutics: &&url </b>
"One of the reasons that brain tumours are such a challenge to treat is because of the difficulties in delivering anticancer drugs across the blood-brain barrier. In fact, the brain is a sanctuary for metastases from tumours that respond to cytostatic drugs, such as paclitaxel, in other parts of the body. In the November issue of the Journal of Clinical Investigation, Fellner et al. report an approach to overcome this barrier, allowing paclitaxel to enter the brain and reduce the size of brain tumours." 

'Paclitaxel is used to treat various tumours, but it is not always effective because it is a substrate for the multidrug-resistance protein P-glycoprotein (P-GP) - a transporter that pumps drugs out of cells. Fellner et al. investigated whether P-GP was expressed in the brain, where it might transport paclitaxel and other drugs away from central nervous system (CNS) tumours. They found that P-GP is expressed at high levels in intact rat and human brain capillaries at the luminal surface of the endothelium - a location that could restrict permeation of drugs into the CNS. When human glioblastomas were transplanted into the brains of mice, the blood vessels that developed within the tumours also expressed high levels of P-GP.' 

"Previous studies have shown that animals with reduced P-GP function accumulate P-GP substrates in the brain, so the authors checked to see whether blocking this transporter increased paclitaxel entry into the CNS. They showed that intravenous administration of the P-GP blocker valspodar increased the levels of fluorescently labelled paclitaxel in the brains of mice. Furthermore, co-administration of valspodar with paclitaxel reduced the growth of human glioblastomas by 90%, whereas treatment with paclitaxel or valspodar alone had no effect on tumour size."  ,,, 
,,, 
Fellner, S. et al. Transport of paclitaxel (Taxol) across the blood brain barrier in vitro and in vivo. J. Clin. Invest. 110, 1309-1318 (2002) 

FURTHER READING Rellin, M. V. & Dervieux, T. Pharmacogenetics and cancer therapy. Nature Rev. Cancer 1, 99-108 (2001) 


Gan To Kagaku Ryoho 1998 Feb;25(3):385-90 
<b>[Pilot study of relapsed osteosarcoma and brain tumor with ifosfamide, carboplatin and etoposide (ICE therapy)] [Article in Japanese]</b>
 Hirota T, Takeuchi M, Iwata A, Kitagawa S, Sato T, Konno K, Sawada K, Kobayashi S, Hamaguchi N, Agata H, Katano N, Fujimoto T. 
Dept. of Pediatrics, Aichi Medical University. 

Ifosfamide, Carboplatin and Etoposide (ICE) therapy was used to treat 4 patients, 2 with refractory osteosarcoma, and one each with relapsed brain tumor and newly diagnosed brain tumor. ICE therapy was administered in doses of Ifosfamide 1,800 mg/m2 x 5, Carboplatin 400 mg/m2 x 2 and Etoposide 100 mg/m2 x 5. A total of 30 courses were administered. Two cases of osteosarcoma had a stable disease (range, 3-9 months) and 2 cases of brain tumor had a complete response by magnetic resonance imaging. ... ICE therapy is highly effective for the treatment of refractory or recurrent solid tumors with acceptable toxicity. 
&&url PMID: 9492832 


Curr Neurol Neurosci Rep 2002 May;2(3):216-24 
<b>Chemotherapeutic dose intensification for treatment of malignant brain tumors: recent developments and future directions. </b>
Kraemer DF, Fortin D, Neuwelt EA. 
Departments of Neurology and Neurosurgery, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97201, USA. neuwelte@ohsu.edu 

...One current focus of research [in treating brain tumors]  is increasing dose intensity of chemotherapeutic agents. Various ways to increase dose intensity include high-dose chemotherapy followed by stem cell rescue (eg, bone marrow transplant), blood-brain barrier disruption or use of RMP7 to increase transvascular drug delivery, local delivery of chemotherapeutic agents (convection enhancement or clysis, antibody conjugates, and biodegradable polymers), chemoprotective agents, and tumor sensitizers. Improved identification of patients likely to respond to a given regimen may also increase the effectiveness of chemotherapy. We also discuss approaches to improve the design of nonrandomized trials by identifying and controlling potential confounding variables. ... 
&&url PMID: 11937000 


Neurosurgery 2001 May;48(5):1033-40; 
<b>Association of total dose intensity of chemotherapy in primary central nervous system lymphoma (human non-acquired immunodeficiency syndrome) and survival. </b>
Kraemer DF, Fortin D, Doolittle ND, Neuwelt EA. Division of Medical Informatics and Outcomes Research, Oregon Health Sciences University, Portland 97201-3098, USA. 

...The importance of enhanced drug delivery in patients with central nervous system (CNS) malignancies has not yet been demonstrated conclusively. Intra-arterial chemotherapy in combination with osmotic bloodbrain barrier disruption (BBBD) increases drug delivery to tumor by 2- to 5-fold and to surrounding brain tissue by 10- to 100-fold as compared with intravenous administration of chemotherapy. 
... In patients with PCNSL, a chemotherapy-responsive tumor type, survival time is highly associated with total drug dose delivered, even in analyses designed to control for potential survival biases. These results probably constitute the strongest evidence to date of the importance of total dose intensity in treating CNS malignancies. 
&&url PMID: 11334269 


Curr Opin Oncol 2000 May;12(3):187-93 
<b>Local drug delivery. </b>
Haroun RI, Brem H. Department of Neurological Surgery, Johns Hopkins Hospital, Baltimore, MD, USA. 

Intensive research efforts are now focused on the development of new strategies for more effective delivery of drugs to the central nervous system. These strategies include chemical modification of drugs, disruption of the blood-brain barrier, and utilization of alternative routes for drug delivery. This paper focuses on local drug delivery for the treatment of brain tumors. It reviews papers published in the past year on local chemotherapy and immunotherapy. Other aspects of local drug delivery are discussed, including convection-enhanced delivery and drug delivery via a controlled-release microchip. 
&&url PMID: 10841189 


J Neurosurg 2000 Apr;92(4):599-605 
<b>In vivo assessment of the window of barrier opening after osmotic blood-brain barrier disruption in humans. </b>
Siegal T, Rubinstein R, Bokstein F, Schwartz A, Lossos A, Shalom E, Chisin R, Gomori JM. Department of Nuclear Medicine, Hadassah Hebrew University Hospital, Jerusalem, Israel. siegal@hadassah.org.il 

Osmotic blood-brain barrier (BBB) disruption induced by intraarterial infusion of mannitol is used in conjunction with chemotherapy to treat human brain tumors. The time course to barrier closure, or the so-called therapeutic window, has been examined in animals but little information is available in humans. ...CONCLUSIONS: Results of these in vivo human studies indicate that the time course to closure of the disrupted BBB for low-molecular-weight complexes is longer than previously estimated. The barrier is widely open during the first 40 minutes after osmotic BBB disruption and returns to baseline levels only after 6 to 8 hours following the induction of good or excellent disruption. These findings have important clinical implications for the design of therapeutic protocols. 
&&url PMID: 10761648 


Neurosurgery 2000 Mar;46(3):704-9 
<b>Enhanced delivery improves the efficacy of a tumor-specific doxorubicin immunoconjugate in a human brain tumor xenograft model. </b>
Remsen LG, Trail PA, Hellstrom I, Hellstrom KE, Neuwelt EA. Department of Neurology, Oregon Health Sciences University, Portland 97201, USA. 

To evaluate dose intensification with osmotic blood-brain barrier disruption (BBBD) and the potential use of drug targeting with monoclonal antibody (MAb) BR96 conjugated to doxorubicin (BR96-DOX, now called SGN15) for treatment of intracerebral and subcutaneous human LX-1 small cell lung carcinoma xenografts in rats. ,,, 
RESULTS: Both BR96-DOX and MAb BR96 treatment resulted in significant regression of subcutaneous tumors, in contrast to control groups including doxorubicin alone, saline, or nonbinding doxorubicin immunoconjugate. BR96-DOX delivered with BBBD to brain tumors with low antigen expression resulted in significantly (P < 0.001) increased rat survival time compared with animals that received intravenous or intra-arterial BR96-DOX. 
CONCLUSION: The combination of an effective drug such as doxorubicin with a MAb to facilitate tumor-selective localization and osmotic BBBD to increase tumor delivery may have practical application in the clinic, because an increased delivery of drug to tumor can be obtained without increasing the dose of systemic drug. 
&&url PMID: 10719867 


Neuro-oncol 2000 Jan;2(1):45-59 
<b>The blood-brain and blood-tumor barriers: a review of strategies for increasing drug delivery. </b>
Groothuis DR. Evanston Northwestern Healthcare, Department of Neurology, Northwestern University Medical School, IL 60201, USA. 

,,,[Approaches to circumvent the BBB] can be divided into two categories: those that attempt to increase drug delivery of intravascularly administered drugs by manipulating either the drugs or capillary permeability, and those that attempt to increase drug delivery by local administration. Several strategies have been developed to increase the fraction of intravascular drug reaching the tumor, including intra-arterial administration, barrier disruption, new ways of packaging drugs, and, most recently, inhibiting drug efflux from tumor. When given intravascularly, all drugs have a common drawback: the body acts as a sink, and, even in the best situations, only a small fraction of administered drug actually reaches the tumor. A consequence is that systemic toxicity is usually the dose-limiting factor. When given locally, such as into the cerebrospinal fluid or directly into the tumor, 100% of an administered dose is delivered to the target site. However, local delivery is associated with variable and unpredictable spatial distribution and variation in drug concentration. The major dose-limiting factor of most local delivery methods will be neurotoxicity. The relative advantages and disadvantages of the different methods of circumventing the blood-brain barrier are presented in this review, and special attention is given to convection-enhanced delivery, which has particular promise for the local delivery of large therapeutic agents such as monoclonal antibodies, antisense oligonucleotides, or viral vectors. 
&&url PMID: 11302254 


Neurosurgery 2000 Jan;46(1):51-60; 
<b>Cognitive outcomes and long-term follow-up results after enhanced chemotherapy delivery for primary central nervous system lymphoma. </b>
McAllister LD, Doolittle ND, Guastadisegni PE, Kraemer DF, Lacy CA, Crossen JR, Neuwelt EA. Department of Neurology, Oregon Health Sciences University, Portland 97201, USA. 

OBJECTIVE: Patients with non-acquired immunodeficiency syndrome-related primary central nervous system lymphomas have the potential to achieve durable complete responses without radiotherapy, with treatment using enhanced chemotherapy delivery with blood-brain barrier disruption (BBBD). Reported 5-year survival rates with combined chemotherapy and radiotherapy were generally only 9 to 22% and were associated, in one study, with an overall 32% incidence of overt dementia and ataxia, which are dramatically increased among patients more than 60 years of age. ,,, RESULTS: The estimated 5-year survival rate for this group was 42%, and the median survival time was 40.7 months. Overall, ,, 36 patients continued to exhibit complete responses after 1 year of BBBD-enhanced chemotherapy ,,, [and] none demonstrated evidence of cognitive loss in neuropsychological tests and/or clinical examinations. 
CONCLUSION: BBBD-enhanced chemotherapy delivery, without subsequent radiotherapy, resulted in favorable survival and cognitive outcomes for patients with primary central nervous system lymphomas who had not previously undergone irradiation. ,,, Clinical Trial 
&&url PMID: 10626935 


Drug Resist Updat 1999 Feb;2(1):30-37 
<b>Causes of drug resistance and novel therapeutic opportunities for the treatment of glioblastoma. </b>
Nagane M, Huang HJ, Cavenee WK. 
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, USA 

Copyright 1999 Harcourt Publishers Ltd. 
&&url PMID: 11504467 
