jaringan kompleks patofisiologi leimioma uteri
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patofisiologi leiomioma uteriTRANSCRIPT
JOURNAL READING JARINGAN KOMPLEKS DARI BEBERAPA FAKTOR DALAM PATOGENESIS LEIOMIOMA UTERI
KEPANITERAAN KLINIK ILMU KEBIDANAN DAN KANDUNGAN
FAKULTAS KEDOKTERAN UKRIDARUMAH SAKIT UMUM DAERAH TARAKAN
Nama Mahasiswa : Mohd Asrul B. Che RahimNIM : 112012059Nama Pembimbing : Dr Harianto Wijaya, Sp.OG
Jaringan yang Kompleks dari beberapa faktor dalam Patogenesis Leiomioma Uteri
Pendahuluan
Leiomioma uteri(fibroids atau myomas) adalah satu-satunya tumor jinak uterus yang paling
sering diindikasikan untuk di operasi hysterectomy. Leiomioma uteri secara klinikal timbul
pada 25% dari wanita dalam umur reproduktif dan menyebabkan morbiti seperti perdarahaan
berat atau memanjang pada menstruasi,nyeri pada pelvic dan disfungsi reproduksi. Tatalaksana
yang definitif untuk tumor fibroid adalah operasi, dan beberapa teknik invasif yang minimal.
Estrogen dan Progesteron merupakan promoter pertumbuhan fibroid. Namun growth factor,
cytokines dan chemokines juga diduga effektor yang potensial terhadap estrogen dan progestron.
Tambahan pula perubahan genetik,mekanisme epigenetic dan komponen matriks extraselular
diduga penting dalam inisiasi dan perumbuhan tumor ini.
Tumor uterus fibroid dan prevelensi ras.
Prevelensi leimioma uteri adalah 3 kali lipat pada wanita berkulit hitam dari wanita berkulit
putih.Faktor lain seperti menarche yang awal,umur(usia reproduktif yang
telat),keturunan,nulliparitas,obesitas,sindrom polikistik ovari,diabetis,hipertensi dan konsumsi
alkohol mempunyai faktor meningkatkan risiko berkembangnya leiomioma uteri.
Faktor genetik
Leiomioma uteri adalah tumor yang indipenden dan monoclonal;pertumbuhan tumor berasal dari
1 sel miometrial yang mutasi. Defek keturunan dari gene fumarate hydratase (FH),Birt-Hogg-
Dube (BHD) dan tuberous sclerosis complex 2 akan mengkontribusi terhadap perkembangan
tumor ini.Penelitian menunjukkan perbedaan pada perubahan genetik pada leimioma seperti
delesi kromosom trisomy, translokasi kromosom dan monosomi kromosom ❑22,25,28,29,30,31.
Tambahan El Gharib et al❑32 menemukan kelainan kromosom klonal pada lima kromosom
berbeda (2,7,8,12 dan 22) . Baru-baru ini Cha et al.33 telah mengidentifikasi tiga loci pada
kromosom 10q24.33,22q13.1, dan 11p15.5 yang berasosiasi dengan kerentanan terhadap uterine
fibroid.
Dengan konsistensi alterasi genetik kromosom dengan tempat yang tertentu,beberapa kandidat
gene telah diidentifikasi HMGA2 sering diekspresi pada leiomioma uteri, dengan penyusunan
kembali kromosom 12q15 ❑34,35,36,yang mana target gene nya let -7 famili (microRNAs)
(miRNAs) dan ditemukan disupresi oleh let-7 secara in-vitro❑37,38. Tambahan pula RAD1L1,
adalah kandidat pasangan translokasi HMGA2 pada leiomioma ❑39,40,41. Baru-baru ini ekspresi
mRNA HMGA1 lebih tinggi telah diobservasi berbanding dengan tumor normal secara
sitogenetik dengan alterasi 6p21❑42. Beberapa gene kandidat, seperti PCOLCE,ORC5L dan
LHFPL3,telah dipetakan pada interval kritikal pada kromosom 7q22❑43,44. Baru baru ini
penjelasan secara komprehensif terhadap alterasi genetik (mutasi MED12) pada leiomioma uteri
telah dilaporkan oleh berbeda-beda kumpulan 45,46,47,48,49,50. Mediator Complex subunit 12
(MED12) adalah komponen mediator kompleks yang mempunyai peran regulator pada aktiviti
RNA polimerase II. MED12 mempunyai prean pada aktivasi transkripsi dab represi dan terlibat
pada banyak proses pekembangan. Makinen dan teman-teman menemukan bahwa gene MED12
telah bermutasi pada frekuensi tinggi (70%) pada leiomioma uteri didapat pada pasien yang
berasal dari Finland (Caucasian). Semua mutasi ini berkluster pada exon 2, dengan lapan mutasi
yang men codon 44. Pola yang sama mutasi MED12 exon 2 juga ditemukan pada pasien berasal
dari Afrika Selatan.❑45
Baru-baru ini Je et al.❑47 menemukan studi tentang MED 12 pada 1862 sampel termasuk
leiomioma,pelbagai carcinoma leukemia sarkoma dan tumor stromal lain-lain,yang mana
ditemukan kadar frekuensi tinggi MED 12 tetapi hanya 1 pada tumor maligna. Temuan ini ❑47
dan temuan sebelumnya❑45,46 menyarankan bahwa mutasi MED12 exon 2 mungkin tisu spesifik
terhadap leiomioma uteri.Namun baru-baru ini studi lain merekomendasi kan bahwa mutasi ini
tidak hanya pada tumor jinak, pengkaji menemukan bahwa 11% tumor otot yang bepotensi
maligna dan 20% leiomiosarkoma uteri ada mutasi MED12.❑50.
Markawski et al ❑48. Mendemonstasikan bahwa mutasi MED 12 pada leiomioma uteri
kebanyakan diasosiasikan dengan karyotipe normal tumor. Kumpulan ini juga menemukan
bahwa tumor dengan mutasi MED12 mengekspresikan mRNA WNT 4 pada kadar lebih
tinggi,menunjukkan bahwa mutasi MED 12 mungkin terlibat dengan aktivasi jalur Wnt.❑48
Namun hasil imunohistokimia menunjukkan bahwa tidak ada asosiasi antara status MED 12
dan B-catenin nuclear/ lokalisasi sitoplasmik❑50
Faktor epigenetik
Epigenetik adalah semua perubahan diturunkan dalam ekpresi gen yang tidak dikodekan dalam
urutan DNA
DNA Methylation
Deoxyribonucleci acid methylation berlaku pada karbon ke -5 cytosine,Metilasi ini berlaku
dipelbagai proses perkembangan dengan menghilangkan,mengalih dan menstabilkan
gen.Ketidakseimbangan ekspresi DNA Metil transferase dijumpai pada leimioma uteri
berbanding di miometrium yang sehat.
Modifikasi histone
Modifikasi histone adalah faktor epigenetik kedua terpenting dalam peran meregulasi ekspresi
gene. Protein histone bisa dimodifikasi dalam pelbagai cara pada N terminal,termasuk
asetilasi,fosforilasi metilasi,deaminasi isomerisasi proline dan adenosinosine difosfat ribosilasi.
Histone deasetilasi 6(HDAC6) adalah faktor regulator dalam jaringan pengangkutan endokrin
dan mempunyai aktiviti deasetilasi histone..❑ Menurut penelitian Wei et al. ❑64 menguji ekspresi
HDCA6 dan peran patologi nya terhadap leiomioma uteri. Mereka menemukan pola
peningkatan HDAC6 dan ekspresi ER-α dalam sampel leiomioma.
Dapat dikenalpasti bahawa modifikasi epigenetik diperlukan semasa perkembangan dan
memainkan peran penting dalam diferensiasi selular dan tissue normal perkembangan menjadi
dewasa. Namun sewaktu stadium penting dalam perkembangan,eksposur lingkungan boleh
merubah keadaan genom yang terkait dengan program deferensiasi sel atau organ,dengan itu
mengalakkan kerentanan terhadap penyakit ini diwaktu kemudian kehidupan. Penelitian
melaporkan melalui efek nongenomik terhadap program ulang pembentukan uterus,estrogen
dari linkungan merekrut regulator epigenetik EZH2 dan mengurangkan kadar histone represif
dalam kromatin dan mempromosikan tumorigenesis di uteri.
Micro RNA
Micro RNA adalah non protein coding yang meregulasi banyak proses biologi dengan
merencanakan miRNA untuk pembelahan atau represi translasi . Penelitian menunjukkan
beberapa mRNA termasuk let7,miR-21,miR-93,miR 106b dan miR 200 dan target gene mereka
secara signifikan di disregulasi pada leiomioma uteri berbanding miometrium normal. Pan et al.
melaporkan bahawa miR-21 di ekspresikan berlebihan pada leiomioma, dengan peningkatan
spesifik waktu fase sekretorik pada siklus menstruasi pada wanita yang menggunakan
kontrasepsi oral. Zavadil et al meneliti korelasi pola global antara ekspresi miRNA yang diubah
dengan predicted target genes pada leiomioma uteri dan miometria. Mereka menemukan jumlah
miRNA didisregulasi secara korelasi terbalik dengan targetnya pada tingkat protein. Pola asosiasi
terbalik miRNA dengan ekspresi mRNA pada leiomioma uteri menunjukkan penglibatan
pelbagai kandidat jalur,termasuk jalur extensive transcriptional reprogramming,cell
proliferation control,mitogen activated protein kinase MAPK transforming growth factor (TGF)-
β,WNT, Janus Kinase/signal trasnduser dan activator of transcription signalling, remodelling
perlekatan sel dan sel-sel dan sel-matrix contacts.
Estrogen
Estrogen mengeluarkan efek fisiologis terhadap target sel nya dengan mengikat ke Estrogen
receptor (ER-α)dan Estrogen receptor –β (ER-β). Estrogen dan reseptornya memainkan peran
penting dalam fisiologi miometrium dan pertumbuhan leiomioma uteri. Beberapa kumpulan
peneliti menemukan mRNA dan protein expression level of ER –α ( diekspresi lebih tinggi) dan
ER-β adalah lebih tinggi pada leiomima uteri berbanding miometrium normal. Penelitian terbaru
menunjukkan estrogen boleh mempertahankan kadar Progestron receptor (PR) dan dengan
demikian progestron melalui reseptornya dapat menggalakkan pertumbuhan leiomioma.
Estrogen secara signifikan mengurangkan ekspresi p53 ( protein supresor tumor). Estrogen dapat
meransang proliferasi sel leiomioma dengan meregulasi ekspresi faktor pertumbuhan dan
dengan mengaktivasi jalur sinyal. Estrogen juga mencetuskan pengaktifan cepat dan sementara
jalur MAPK pada sel leiomioma. Estrogen juga menghasilkan fosforilasi protein tyrosine pada
protein intraselular
Progesterone
Progesteron bekerja dengan berinteraksi dengan reseptor progesterone α dan reseptor reseptor β
(PRβ) Progesterene dan reseptornya memainkan peran dalam proses biologi leiomyoma dan
miometrium. Penelitian menunjukkan kadar progesterone dan mRNA pada leiomioma lebih
tinggi dari miometrium. Fujimoto et al. menemukan ekspresi mRNA PRβ relatif lebih pada
permukaan leiomyoma.Ini menunjukkan ekspresi predominan PR-B pada bagian ini adalah
fenotip aktif untuk proliferasi progestasi yang berkaitan dengan pertumbuhan leiomioma.
Progesterone dapat menstimulasi pertumbuhan sel leiomioma dan ketahanan hidup sel dengan
meningkatkan regulasi sel limfoma B ekspresi (Bcl)-2 protein dan menurunkan regulasi ekspresi
tumor necrosis factor (TNF) α
Growth factors
Growth factor adalah protein atau peptida yang diproduksi oleh sel otot polos dan fibroblas yang
turut berperan dalam beberapa aktivitas selelur seperti proliferasi, sintesis ECM dan angiogenesis
yang penting untuk pertumbuhan leiomioma. Beberapa growth factors seperti EGF,Heparin
binding EGF,PDGF,IGF, TGF- α ,TGF-β vascular endothelial growth factor (VEGF) , acidic
firbroblast growth factor(FGF) dan reseptor masing-masing growth factors,dilaporkan
memainkan peran dalam pertumbuhan leiomioma. Activin dan miostatin adalah protein yang
diindentifikasi pada leiomioma dan miometrium.
Sitokin
Sitokin adalah protein yang dilepaskan oleh sel sistem imun . Sitokin menghantar sinyal
intraselular dengan mengikat specific cell-surface receptor 151,152.
Beberapa interleukin (IL) telah diidentifikasi dalam patofisiologi miometrium. Termasuk IL-
1,IL-, IL 11, dan IL 13,kerna ekspresi berlebihan sitokin berikut bertindak sebagai kunci
regulator kepada subepithelial airway fibrosis. Terutama melalui interaksi dengan TGF-β
156,157,158,159. Ekspresi sitokin tersebut lebih pada leiomioma berbanding miometrium. ILs
menambah ekspresi TNF-α yang ditemukan pada leiomioma relatif pada miometrium normal
dan diturunkan regulasi oleh progesteron.
Chemokines
Chemokines adalah protein yang di ekspresi kan oleh hampir semua sel yang bernukleas.
Chemokines adalah mediator angiogenesis,hematopoiesis dan fibrosis. Monocyte
chemoattractant protein 1 memainkan peran dalam respon inflamasi monosit dan makrofag.
Sozen et al. menemukan chemokine lebih tinggi pada miometrium berbanding leiomioma.
Apabila sel leiomioma diterapi dengan anti-MCP-1 neutralizing antibody,didapati berlaku
proliferasi.Tambahan lagi pada sel leiomioma E2 dan progestin sendiri dan pada kombinasi
mengurangkan kadar MCP-1. Hasil ini menunjukkan MCP-1 mempunyai sifat antineoplastik
pada leiomioma. IL-8 dan reseptor IL-8 tipe A telah diidentifikasi dengan peningkatan ekspresi
pada miometrium berbanding leiomioma dan inhibisi proliferasi sel diobservasi apabila IL-8
diblok oleh antibodi neutral,ini menunjukkan potensi peran IL-8 dalam pertumbuhan tisu
miometrium. Tambahan pula beberapa chemokines dan reseptor chemokines termasuk
macrophage inflammatory protein (MIP)-1α, MIP-1β, RANTES, eotaxin, eotaxin-2, IL-8,
chemokine (cc-motif) receptor 1 (CCR1), CCR3, CCR5, chemokine (cxc-motif) receptor 1
(CXCR1), and CXCR2 mRNA, telah diidentifikasi pada miometrium dan tisu leiomioma,lebih
rendah daripada miometrium.
Komponen ECM
Leiomioma uteri dikarakterisasi oleh kuantiti dan kualitas abnomaliti pada komponen ECM,
terutama kolagen, fibronectin, and proteoglycans. Leiomioma mengandungi 50% lebih daripada
miometrium bersamaan dan berfungsi sebagai reservoir untuk growth factors,sitokin chemokines
angiogenic dan mediator respon inflamasi dan proteases yang diproduksi oleh sel tumor.
Kolagen adalah komponen major pada ECM yang berkontribusi kepada stabilisasi dan
mempertahankan integriti struktur tisu. Namun struktur dan orientasi fibrin kolagen yang
abnormal ditemukan pada leiomioma. Disamping itu ekpresi relatif berlebihan pada mRNA
kolagen tipe I dan III pada leiomioma berbanding miometrium disebelahnya. Tambahan pula
peningkatan ekspresi kolagen tipe I dan V pada tingkat protein ditemukan pada leiomioma
berbanding miometrium yang normal. Malik et al. menguji beberapa seri kolagen subtipe
COL1A1, 4A2, 6A1, 6A2, 7A1, dan 16A1 diekspresikan lebih banyak pada leiomioma
berbanding pada miometrium. Leiomioma uteri pada manusia yang berasal dari fibroblas dapat
menstimulisasi proliferasi sel leiomioma uteri dengan peningkatan produksi kolagen tipe type I,
IGFBP-3, VEGF, EGF, bFGF, PDGF-A and B, TGF-β1, and TGF-β3 dan dapat juga
mengaktifkan reseptor tyrosine kinase dan reseptor sinyal TGF-β. Penemuan ini menunjukkan
bahawa pertumbuhan leiomioma dapat dimediasi oleh mekanisme autokrin atau parakrin. Tumor
yang berasal dari fibroblas dan atau sel leiomioma uteri dapat menggalakkan sintesis growth
factors dan mengaktif kan jalur sinyalnya yang penting dalam menstimulasi proliferasi sel tumor
dan produksi komponen ECM. Penelitian menunjukkan perubahan pada ECM dapat
memodifikasi stress mekanikel pada sel yang menyebabkan aktivasi internal mechanical
signaling dan menyumbang pada pertumbuhan leiomioma. Telah dilaporkan sel leiomioma yang
terpajan pada beban mekanikal dan menunjukkan fitur struktural dan biokimia yang konsisten
dengan aktivasi solid state signalling.Walaupun fitur leiomioma meningkatkan stress mekanikal
sel leiomioma menunjukkan respons melemah pada isyarat mekanikal berbanding pada sel
miometrium. Berdasarkan persoalan ini, Malik et al. mengkarakterisasi integrin dan laminin
kepada sinyal pada sel leimioma.Hasil eksperimen mereka menunjukkan hasil bahwa sinyal
mekanikal yang dilemahkan pada sel leiomioma diikuti oleh peningkatan ekspresi dan
ketergantungan pada sinyal integrin β1 pada sel leiomioma berbanding daripada sel miometrium.
Dermatopontin, protein ekstraselular yang mengikat kepada molekul kecil demantan sulfate dan
decorin, diekspresikan pada leiomioma,namum kadar ekspresi berkurang pada leiomioma
berbanding daripada miometrium.Mengingat Leiomioma dan keloid adalah penyakit fibrotik
dan berkongsi kesamaan epidemiologik, kaitan molekular telah dibina antara kedua kondisi
patologik dengan melihat berkurangnya ekspresi dermatopontin (kolagen pengikat protein) dan
struktur fibril kolagen. Disamping itu beberapa analisa mikroarray menunjukkan penurunan
regulasi dermtopontin pada leiomioma berbanding dengan miometrium.
Proteoglikan adalah protein glikosilasi yang terikat secara kovalen pada glikoaminoglikan sulfat
dan bagian penting kepada struktur leiomioma. David et al. menemukan kadar glikoaminglikan
dan versican ( proteoglikan ECM besar) yang tinggi pada fibroid uteri,namun kadar dekorin yang
relatif rendah pada fibroid uteri dan keloid berbanding tisu normal. Penemuan ini konsisten
dengan penemuan sebelumnya yang berkaitan dengan ikatan molekular antara kedua jenis
penyakit fibrotik ini. Tambahan pula beberapa penelitian menunjukkan kadar ekspresi versican
adalah lebih tinggi pada leiomioma berbanding daripada miometrium. Pelbagai ekspreis
glikosaminoglikan dan proteoglikan juga ditemukan pada leiomioma dan miometrium.
Fibronectin adalah glikoprotein ECM yang mengikat kolagen kepada integrin.Terdapat Kadar
ekspresi mRNA fibronectin pada pelbagai patofisiologi miometrium. Stewart et al. menemukan
tidak ada perbedaan yang signifikan atara leiomioma dan miometrium pada apa pun tahap pada
siklus menstruasi.Namun Arici and Sozen menemukan peningkatan kadar ekspresi fibronectin
pada leiomioma berbanding daripada autologous miometrium. Menariknya, kumpulan ini turut
melaporkan bahwa TGF-β3 menginduksi ekspresi fibronectin pada leiomioma dan secara
lansung menstimulasi sel miometrium dan leiomioma pada kultur berpoliferasi.
Tissue remodelling yang melibatkan ECM turnover memainkan peran penting pada
pertumbuhan dan regresi leiomioma,dimana diregulasi oleh kombinasi aksi oleh matriks
metalloproteinase (MMP) (protein yang memecahkan ECM) dan tissue inhibitor of MMPs
(TIMPs). Khususnya beberapa bentuk dari mRNA MMPs dan TIMPs dan protein telah
ditemukan diekspresikan secara berbeda pada miometrium dan leiomioma. Baru-baru ini analisis
mikroarray menunjukkan perubahan pada array secara meluas pada MMP pada tisu leiomioma.
Sel Kandidat untuk perkembangan dan pertumbuhan fibroid
Dengan mempertimbangkan bahwa fibroid uteri adalah sangat lazim dan mempengaruhi wanita
pada usia reproduksi (adanya siklus menstruasi) menambahkan lagi kepercayaan bahwa cedera
yang berhubungan dengan dengan mens dapat menyebabkan respon inflasmasi yang tidak
benar, ini membawa kepada pembentukan fibroid uteri. Kontraksi miometrium pada akhir
perdarahan menstruasi dapat menginduksi cedera iskemi atau cedera iskemi-reperfusi pada
otot polos miometrium yang mungkin menjadi kandidat untuk sel progenitor dari fibroid uteri.
Untuk mendukung hipotesis ini, sel apoptotik positif , sel positif p53 dan sel positif 21 telah
ditemukan hanya pada fase folikuler pada siklus menstruasi. Namum sel positif Ki-67 yang
dilihat terutama pada fase luteal siklus menstruasi. Hasil ini memberi kesan bahwa majoriti dari
sel yang rusak kelihatan dieliminasi pada fase folikuler siklus menstruasi, dieliminasi sebagai sel
apoptotik , tetapi beberapa sel yang rusak bisa bertahan hidup dengan menerima mekanisme
pertahanan terhadap stress oxidatif dan apoptosis. Sel ini mungkin adalah progenitor kepada
fibroid uteri. Bahkan sel leiomioma uteri menpunyai mekanisme proteksi terhadap stress
mekanisme yang mengekspresi manganase superoxide dismutase (MnSOD) dan terhadap
apoptosi Bcl-2, PEP-19(protein sel Purkinje 4 PCP4) dan secreted frizzled related protein1
(sFRP1)
Telah dipersetujui bahwa menstruasi ovulasi dan parturitas menyebabkan kecederaan fisiologi
yang mencetuskan reaksi inflamasi pada uterus. Sel Miofibroblas diaktifkan oleh inflamasi dan
transformasi selular inilah yang menjadi peristiwa penting untuk pemulihan homeostasis tisu dan
proses penyembuhan luka. Miofibroblas dikarekterisasi oleh pertambahan
proliferasi,kebolehan bermigrasi, produksi sitokin dan kapasitas untuk menghasilkan matriks
interstitial. Namun fungsi miofiblas yang tidak tepat telah ditunjukkan dapat menyebabkan
fibrosis,oleh kerana memiliki sifat ketidakmampuan regenerasi tisu,selalu menghasilkan kolagen
kolagen dan parut kaku.. Transformasi miofibroblas dapat berlaku dari sel berbeda tipe,kerna
miometrium mengandungi sel otot polos , jaringan ikat fibroblas,stem sel,sel vascular dan
progenitor sel berasal dari sumsum tulang. Baru- baru ini penelitian mengenai stem sel telah
membuka kemungkinan baru untuk memahami pertumbuhan uterine fibroid.
Kesimpulan dan perspektif masa hadapan.
Uterine fibroid umumnya berhubungan dengan perdarahan menstruasi yang memanjang, berat
dan nyeri pelvis. Namun tumor ini juga mempunyai efek negatif terhadap fertilitas dan hasil
kehamilan untuk pasien yang ingin mengikuti assisted reproductive technology (ART). Namun
literatur berkaitan dengan leiomioma uteri dan kesan nya kepada ART adalah membingungkan.
Tambahan pula prevelensi tinggi leiomioma uteri dan pengaruh potensinya yang merugikan
terhadap ART dan fungsi reproduksi. Ini menjamin penelitian yang dirancang teliti diteruskan
untuk memastikan etiologi,terapi optimal dan terapi baru yang kurang morbiditasnya.
Perbedaan ras dan faktor risiko lain,faktor genetik,mekanisme epigenetik, estrogen, progesteron,
growth factors,sitokin,chemokines. Dan komponen ECM telah dikenalpasti memberi kesan
kepada biologi miometium dan leiomioma. Beberapa dari faktor tersebut boleh dipertimbangkan
untuk membina strategi terapi untuk menghalang transformasi miometium dan/ atau
pertumbuhan miometrium. Sehingga sekarang terapi yang mungkin telah diuji secara klinikal
dan beberapa masih sedang dikaji pada biologi leiomioma.
Untuk menimbang perubahan genetik pada leiomioma berbanding miometrium,terapi gene
dapat menjanjikan target untuk menghentikan pembentukan leiomioma.Laporan telah
menunjukkan terapi dengan adenovirus mediated herpes simplex virus thymidine
kinase/ganciclovir menginhibisi proliferasi petumbuhan leiomioma pada manusia dan tikus dan
mengurangkan volume fibroid uteri pada model tikus Eker. Tambahan pula, Ad- mediated
delivery of a DNER (dominant negative E receptor) gene juga mengecilkan tumor leiomioma
uteri pada tikus Eker.
Selain faktor genetik,pemahaman tentang status metilasi DNA dan modifikasi histone pada
patogenesis leiomioma uteri adalah kritikal dalam mengembangkan terapi epigenetik yang akan
memulihkan modifikasi reguler pola epigenetik dengan menginhibisi enzim epigenetik modifier
( DNA methltransferases, demethylases, and histone deacetylases). Dengan munculnya miRNA
sebagai kunci regulator kepada kestabilan ekspesi gene,ini akan lebih menarik untuk diselidiki
tentang potensi peran regulasi miRNAs terhadap target gene terpilih.yang dimana produknya
dapat mempengaruhi pertumbuhan leiomioma.
Dengan mempertimbangkan peran paling penting hormon seks steroid pada pertumbuhan
leiomioma, GnRH agonis telah diluluskan oleh US Food and Drug Administration kerana
mengurangkan volume fibroid dan simptom yang terkait. US Food and Drug Administration
juga telah meluluskan alat intrauterine levenorgestrel-releasing intrauterine system (Mirena)
(Bayer Schering Pharma, Germany) sebagai tambahan untuk merawat perdarahan berat pada
pengguna alat sahaja.Tambahan lagi beberapa terapi yang mungkin terutama antiprogestin
(mifepristone) dan selective Progesterone receptor modulators (asoprisnil, CDB-2914, and CDB-
4124) telah menunjukkan hasil teraputik yang efesien dan sekarang diuji klinis (www.fda.gov).
Karena sistesis estrogen aromatase dan diekspresi berlebihan pada leiomioma berbanding
miometrium pada African American relatif kepada Caucasian American dan wanita jepang
beberapa aromatase inhibitors (letrozole, anastrozole, and fadrozole)telah diuji terhadap
leiomioma. Sehingga sekarang, trial klinik (fase 1) terhadap letrozole telah ditarik. Namun trial
klinikal fase III terhadap anastrozole telah direkrut.
Namun beberapa terapi medikal (GnRH antagonists, raloxifene, cabergoline, danazol gestrinone,
and lanreotide) telah gagal dalam mencapai efektifitasnya terhadap regresi fiboid dan simptom
yang berkatian dengan firboid. Terbukti bahwa growth factor, sitokin dan kemokin
dipertimbangkan sebagai efektor potensial estrogen dan progesteron terhadap pertumbuhan
leiomioma. Growth factor, sitokin dan kemokin mengawal beberapa proses biologi seperti
proliferasi sel,remodelling ECM,angiogenesis dan apoptosis,yang mana merupakan penting
dalam pertumbuhan leiomioma. Oleh itu adalah jelas bahwa growth factor, sitokin dan kemokin
boleh dipetimbangkan sebagai target major dalam mengawal pertumbuhan leiomioma,
Karena EGF telah ditunjukkan dapat memediasi kerja estrogen dan memainkan peran dalam
meregulasi pertumbuhan leiomioma. AG1478 dan TKS050 (EGFR blocker) telah ditunjukkan
efektif dalam memhentikan pertumbuhan sel leiomioma.TGF-B juga mempunyai peran kritikal
terhadap pertumbuhan sel leiomioma. Bukti dari model hewan coba yang rentan secaa genetik
juga menunjukkan bahwa Sinyal TGF-B adalah kritikal untuk mempertahankan penyakit ini.
Oleh kerna itu telah ditemukan bahwan inhibitor selektif terhadap TGF-βRI menurunkan
jumlah insidens dan saiz dari tumor ini.
Dengan mempertimbangkan bahwa leiomioma dikarekterisasi oleh pertambahan proliferasi sel
dan tisu fibrosi, antiproliferasi dan atau agen anti fibrotik boleh menjadi target untuk terapi
leiomioma. Awalnya beberapa campuran termasuk pirfenidone (235), CP8947 (236),
rosiglitazone (237), ciglitizone (238), halofuginone (239), tranilast semua-trans retinoic acid 242,
243, heparin (244), isoliquiritigenin (245), curcumin 246, 247 dan vitamin D 248, 249, 250,telah
menunjukkan efek antiproliferatif dan efek antifibrotik terhadap sel leiomioma. Dari semua ini
trial klinik fase 2 terhadap perfenidone telah selesai. Vitamin D menunjukkan hasil yang baik
terhadap efektifitas terapi. Vitamin D menginhibisi proliferasi sel leiomioma melalui supresi
terhadap COMT. Polimorfisme COMT dan asosiasinya terhadap uterine fibroid adalah lebih
tinggi pada African American berbanding wanita berkulit putih atau wanita hispanik Tambah3an
lagi defisiensi vitamin D adalah lebih banyak pada African American berbanding European
American. Vitamin D juga mengurangkan ekspresi gene TGFβ3 induced fibrosis related pada
sel leiomioma. Tambahan lagi vitamin D mengecilkan saiz tumor pada model tikus Eker.
Epigallocatechin gallate yang ditemukan pada teh hijau (Camellia sinensis),secara invitro
menunjukkan berlaku apoptosis dan efek inhibisi terhadap proliferasi sel leiomioma.
Eksperimen in vivo menunjukkan bahwa epigallocatechin gallate mengurangkan volume dan
berat tumor pada tikus percobaan. Trial klinik rehadap epigallocatechin gallate juga telah selesai.
Masih didalam investigasi bahwa leiomioma adalah hasil daripada respon inflamasi yang tidak
benar,oleh itu anti-inflamasi (alami atau sintetik) adalah agen efektif untuk tumor jinak ini.
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