MELEWATI SAWAR

DARAH OTAK TUMOR

UNTUK PENGOBATAN
GLIOBLASTOMA
YANG EFEKTIF
 ABSTRAK
Gliomas are the most common primary brain tumor. Especially
in adult patients, most gliomas belong to a heterogeneous
group of diffuse gliomas, namely glial tumors characterized by
diffuse infiltrative growth in pre-existing brain tissue.
Unfortunately, glioblastoma, the most aggressive diffuse glioma
(WHO grade IV) is also the most frequent. After standard
treatment, the overall 2-year survival of glioblastoma patients is
around only 25%.
Unfortunately, glioblastoma multiforme (GBM) patients
have not benefited because although many
experimental drugs have been tested in clinical trials,
all have failed miserably. The grim prognosis for GBM
is at least in part due to a lack of drug delivery that
successfully passes the tumor blood brain barrier
(BBTB)
 GLIOMA

• Gliomas represent about 80% of all tumors that arise in brain tissue, with an
incidence of around 7 per 100,000 people worldwide. Patients with glioma
can experience several neurological symptoms such as headaches, seizures,
focal neurological deficits, memory loss, personality changes, vomiting, and
visual changes. malignancy level (grade I = glioma variant, grade II = low
level diffuse glioma; grade III = malignant / anaplastic diffuse glioma; grade
IV = glioblastoma)
• Primary and secondary glioma
 KOMPOSISI MOLEKUL BBB DAN IMPLIKASI
UNTUK MASUKNYA OBAT
•
Glioblastoma consists of various regions which are
characterized by various levels of integrity of BBTB.
Heterogeneous BBTB integrity can be found throughout
glioblastoma, varying from being fully compromised in large
tumor areas (left panel) to slightly leaking in more invasive
peripheral areas (middle panel) or even completely intact in
areas that are attacked rarely far from tumor tumors ( right
panel)). Where BBTB is compromised by macromolecules (eg
antibodies) and compounds that are normally efficiently
confined to the brain by transport efflux can extravasate and
involve glioma cells, intact BBTB protects isolated tumor cells
isolated from efficient delivery of therapy. This protection has
strong implications for the efficacy of anti-tumor treatment,
especially given the fact that this area cannot be operated on
and often causes recurrent tumors
 A. The blood-brain barrier consists of
physical and physiological barriers, where
the physical components consist of tight
junctions (TJ), gap junction (GJ) and junction
of adherens (AJ) which together limit
paracellular exchange between blood and
blood. brain and allows endothelial cells to
work together closely by providing a channel
for direct exchange of cytoplasm. Strict
junction is under regulation by the
bradykinin receptor to maintain a strict
barrier character.
B. Strategies against various intact BBB
modalities have been developed to increase
the delivery of therapy to the brain
 SAWAR DARAH OTAK TUMOR (BBTB)

• The high metabolic demands of high-grade gliomas create an area of hypoxia

which triggers an increase in expression of Vascular Endothelial Growth Factors
(VEGF) and angiogenesis, which leads to abnormal blood vessel formation and
dysfunctional BBTB. Importantly, however, the invasive potential of gliomas
causes the proliferation of high-grade glioma cells outside the disturbed BBTB
region and within the normal brain area, where the barrier function is still
(more) still intact. Usually, this includes areas that do not show gadolinium
enhancement on T1 weighted MRI. As a result, both low and high level gliomas,
BBB and BBTB barriers form a major obstacle in the treatment of brain tumors by
preventing the delivery of sufficient quantities of potentially effective
therapeutic agents.
 MENGHINDARI ATAU MELEWATI BBTB

• Osmotic blood- brain barrier distruption (BBBD)

This strategy called Blood Brain Barrier Disruption (BBBD) is based on intra-
arterial infusion of a mannitol hyposmotic solution, which causes temporary
shrinkage of endothelial cells and then opens tight junctions for several hours.
This time window can then be used to dispatch intra-arterial chemotherapy
agents such as methotrexate or carboplatin.
• Pembukaan BBTB yang dimediasi reseptor bradykinin
Upaya lain untuk membuka BBTB / BBB yang lebih halus,
didasarkan pada stimulasi reseptor endotel otak yang
menginduksi pembukaan persimpangan ketat melalui
pemanfaatan senyawa seperti bradykinin melalui utusan
kedua. Ini telah menyebabkan perkembangan klinis RMP-7
(Cereport atau labramidil), analog bradykinin dengan
peningkatan paparan sistemik setelah injeksi IV. Alasan
potensial untuk hasil negatif adalah bahwa tingkat dosis
RMP-7 dari 300 ng/kg mungkin tidak memadai. Dan jadwal
pemasukan obat
• Penghambatan transporter eflux obat
Seperti diuraikan di atas, banyak obat menunjukkan penetrasi otak yang
sangat meningkat ketika pengangkut eflux obat tidak ada (seperti yang
diamati pada tikus KO). Konsekuensinya, penghambatan transporter eflux
yang resistan terhadap berbagai obat oleh inhibitor spesifik tampaknya
merupakan strategi yang menarik untuk meningkatkan penetrasi obat ke
dalam otak tanpa mengurangi integritas lapisan endotel dan persimpangan
yang kencang yang mungkin menyebabkan toksisitas seperti terlihat pada
BBBD.
• Mengeksploitasi sistem transportasi yang dimediasi reseptor
Strategi lain untuk meningkatkan penetrasi otak tanpa mengganggu
persimpangan yang ketat dan integritas lapisan endotel adalah dengan
menggunakan mekanisme penyerapan yang dimediasi reseptor. Untuk itu,
faktor angkutan yang menargetkan reseptor (misalnya Reseptor insulin atau
transferrin) di BBB digabungkan dengan obat (misalnya Paclitaxel) atau
kendaraan (mis. Liposome) yang mengandung obat atau radiofarmasi. Baru-
baru ini sebuah makalah yang menarik muncul, menunjukkan bahwa
transporter docosahexanoic Mfsd2a bertindak dengan menekan transcytosis
dalam sel endotel CNS. Mengganggu fungsi atau ekspresinya dapat
meningkatkan transcytosis dan dengan demikian meningkatkan pengiriman
obat melalui rute ini.
• Penghapusan BBTB
Pendekatan yang tampaknya langsung untuk mengatasi BBTB adalah dengan
pengiriman agen terapi langsung ke parenkim otak (tumor) atau ke dalam
rongga reseksi pasien glioma. Injeksi obat intracavitary, dengan penggunaan
sistem intraventrikular / intrakaviter seperti reservoir ommaya,
memungkinkan pengiriman agen kemoterapi langsung ke rongga tumor.
Injeksi terjadi secara perkutan ke reservoir subkutan dan obat kemudian
ditransfer melalui tengkorak ke dalam tumor (rongga) dengan kompresi
manual reservoir. Distribusi obat ditentukan oleh laju dan durasi injeksi dan
difusi.