EFEK KARDIOTOKSIK OBAT KEMOTERAPI DOXORUBICIN

Pendahuluan: Doxorubicin merupakan obat kemoterapi yang banyak digunakan untuk terapi berbagai macam jenis kanker seperti leukemia akut, kanker payudara, kanker tulang dan ovarium. Senyawa ini diisolasi dari streptomyces peucetius var caesius dan digunakan secara luas dalam pengobatan kanker. Namun doxorubicin memiliki efek kardiotoksik yang cukup berbahaya. Disfungsi miokard oleh penggunaan doxorubicin dapat muncul yang diakibatkan oleh terbentuknya radikal bebas yang berbahaya bagi jantung.Pembahasan: Doxorubicin merupakan obat golongan antrasiklin yang paling banyak digunakan dalam pengobatan kanker. Efek samping yang sering timbul akibat penggunaan doxorubicin adalah kardiotoksik. Disfungsi miokard yang diakibatkan oleh doxsorubicinkemungkinan disebabkan oleh radikal bebas yang terbentuk, gangguan fungsi adrenergik, terbentuknya peroksida lipid, gangguan transportasi Ca dalam sarcollemma, lepas TNFα dan interleukin-2 serta sitokin terbebas dari jaringan tumor. Mekanisme stres oksidatif adalah mekanisme yang paling sering mengakibatkan kerusakan jantung. Kesimpulan: Doxorubicin merupakan obat golongan antrasiklin yang banyak digunakan dalam pengobatan kanker. Doxorubicin memiliki efek samping yang cukup berbahaya yakni kardiotoksik. Kardiotoksik yang ditimbulkan dapat menyebabkan gagal jantung. Untuk itu dalam penggunaan doxorubicin harus dilakukan pendekatan klinis dalam memantau efek toksik tersebut.

Identification and enhancing production of a novel macrolide compound in engineered Streptomyces peucetius

Activation of peucemycin in S. peucetius DM07 by the OSMAC strategy.

Transformation of glycosyltransferase dnrs and auxiliary DNRQ genes into the Streptomyces peucetius MH9.2 for the enhance of doxorubicin production

Doxorubicin antibiotic produced by Streptomyces peucetius is a very crucial antibiotic with a large spectrum used as an anticancer drug and in clinical treatment. Production of doxorubicin from wild type strain by microbiological fermentation process is nomally very low yield and limited. The enhancement of doxorubicin production (DXR) by the genetically engineering of the auxiliary genes involved in the pathway of doxorubicin biosynthesis from Streptomyces peucetius has being focused by many research groups. The gene cluster responsible for biosynthesis of doxorubicin had been isolated, sequenced and characterized. Among them, the dnrQ and dnrS genes belong to the gene cluster encoded for the glycosyltransferase and helper enzymes, which are responsible for attachment of sugar moiety to -rhodomycinon intermediate and regulation of doxorubicin production, respectively. In this research, the dnrQ and dnrS genes were isolated and cloned in the p25.1 vector containing the strong promoter (ermE*) to generate the p25.1QS as a recombinant vector. The obtained plasmid was transferred into the host strain Streptomyces peucetius MH9.2 by the protoplast transformation method to generate the S. peucetius MH9.2SQ strain. Doxorubicin production from the recombinant S. peucetius MH9.2SQ and the parent strain were extracted and purified by using chlorofrom and methanol solvents. The products were confirmed by HPLC, LC-mass analysis and antibacterial bioassay. The results showed that the over production of doxorubicin was accumulated by the recombinant strain from the fermentation broth. In the S. peucetius MH9.2SQ, the doxorubicin productivity was 3.1 to 3.6 folds higher than in the parent strain. This recombinant strain could be a potential candidate for further research in enhancement and larger biomass scale of DXR production.

Enzymatic Bioconversion of Cholesterol Using Glucosyltransferase and Methyltransferase Isolated from Streptomyces

A sterol glycosyltransferases (SGT) gene (sav7185; accession number NP_828361) was isolated from Streptomyces avermitilis MA-4680. The full-length gene consists of 1284 nucleotides and encodes 427 amino acids with a calculated mass of 46.05 kDa. The gene was then cloned in pET28a vector and heterologously expressed in Escherichia coli BL21 (DE3) and was used for the biotransformation of cholesterol. This SGT protein showed favorable activity towards cholesterol tested in this study. Further, we tested the conversion of cholesterol to its methoxide using another Streptomyces O-methyltransferase (accession number KF420279). This O-methyltransferase (OMT) SpOMT2884, originating from Streptomyces peucetius ATCC 27952, was cloned, expressed, and applied for the production of methylated derivative. The GC-MS analysis confirmed the conversion of cholesterol into cholesterol-3-O-β-D-glucoside and a novel cholesterol-3-O-methoxide. Hence, these Streptomyces SGT and OMT could find applications for the derivatization of pharmaceutically significant sterols.