Департамент (медицина)
Направленная ферментная пролекарственная терапия ( DEPT ) использует ферменты, искусственно введенные в организм для преобразования пролекарства , которые не имеют или плохой биологической активности, в активную форму в желаемом месте в организме. [ 1 ] [ 2 ] [ 3 ] Многие химиотерапевтические препараты для рака не имеют специфичности опухоли, и дозы, необходимые для достижения терапевтических уровней в опухоли, часто токсичны для других тканей. Стратегии отдела являются экспериментальным методом снижения системной токсичности лекарственного средства, достигая высокого уровня активного препарата только на желаемом участке. В этой статье описываются различия технологии отдела. [ Цитация необходима ]
Терапия пролекарством, направленным на антитело (Adept)
[ редактировать ]Адепт [ 4 ] является стратегией для преодоления проблем отсутствия селективности опухоли . Антитело, разработанное/разработанное против опухолевого антигена , связано с ферментом и вводится в кровь, что приводит к селективному связыванию фермента в опухоли. Когда достаточная дискриминация между уровнями опухоли и нормального фермента ткани является пролекарством в кровообращение, которая преобразуется в активное цитотоксическое препарат ферментом, только внутри опухоли. Селективность достигается путем опухолевой специфичности антитела и задерживая введение пролекарства до тех пор, пока не произойдет большая дифференциала между уровнями опухоли и нормальной тканей. [ Цитация необходима ]
Adept показал противоопухолевую активность в моделях опухоли животных человеческой хориокарциномы и карциномы толстой кишки и молочной железы .
ADEPT history
[edit]The first pilot-scale clinical trial of ADEPT was carried out at Charing Cross Hospital, London, using an anti-CEA F(ab′)2 antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2).[5]
The antibody used in the first ADEPT clinical trial was of murine origin and the enzyme was bacterial. Host antibodies to both components of the AEC were present in the blood of all non-immunosuppressed patients by day 10 after AEC infusion.[6] Several patients received ciclosporin since it had been shown in rabbits that this could delay the appearance of host antibodies to soluble proteins.[7]
A subsequent, small-scale trial at the Royal Free Hospital, London, used the same agents as in the Charing Cross Hospital trial but the protocol was modified to provide additional pharmacokinetic data and most patients received only a single course of treatment.[8]
Gene-directed enzyme prodrug therapy (GDEPT)
[edit]GDEPT is a suicide gene therapy in which the enzyme required for prodrug conversion is produced within the target cell, using a gene delivered to it by gene therapy. When an adequate differential exists between the targeted cell and endogenous tissue, non-toxic prodrug is administered and is subsequently converted into its toxic form within the target cell.[9] Systems that use viral vectors to deliver the gene are known as VDEPT.
Virus-directed enzyme prodrug therapy (VDEPT)
[edit]![[икона]](http://upload.wikimedia.org/wikipedia/commons/thumb/1/1c/Wiki_letter_w_cropped.svg/20px-Wiki_letter_w_cropped.svg.png){kind=small} | This section needs expansion. You can help by adding to it. (May 2013) |
VDEPT is the term given to the use of a virus to deliver the gene for GDEPT. VDEPT can potentially be used to enhance the therapeutic potential of oncolytic viruses.
Lectin-directed Enzyme-Activated Prodrug Therapy (LEAPT)
[edit]LEAPT is a variant of DEPT in which the manipulation of carbohydrates on the surface of the enzyme is used to target the enzyme activity to the cell in question.[10] This allows exploitation of the sometimes highly specific sugar-lectin interactions found in organisms, including humans. Proof-of-principle examples have shown delivery to target organs of enzymes that specifically release cytotoxics to treat tumours.
Polymer-directed enzyme prodrug therapy (PDEPT)
[edit]PDEPT uses polymer-drug conjugates, drugs contained within a polymer 'shell' such as pHPMA and designed to be released only by a specific enzyme.
Clostridia-directed enzyme prodrug therapy (CDEPT)
[edit]CDEPT is the use of Clostridia to convert prodrugs into active drug agents. CDEPT exploits the hypoxic environment of solid tumors to target drugs to tumors using anaerobic bacteria resident in the tumour to convert the pro-drug to the active form.[11][12] Intravenously injected clostridial spores exhibit a specificity for tumours, colonising the hypoxic areas of the tumours.[13]
The CDEPT strategy
[edit]Perhaps the most challenging issue in cancer treatment is how to reduce the side effects of the injected anti-cancer agents, which are of a high cytotoxicity potential. A widely used solution is to use enzymes which are able to convert a relatively non-toxic prodrug precursor into the active drug form(s). Clostridial-directed enzyme prodrug therapy (CDEPT)[14] is one of the possible approaches.
Solid tumors, in contrast to normal tissues, grow rapidly. As a result, the cancerous tissues may suffer from inadequate blood and oxygen supply.[15] Therefore, clostridia can grow in tumor and destroy it specifically.[16] (Originally, Parker and co-workers[17] showed that the injection of Clostridium histolyticum spores to the transplanted sarcomas of mice results in significant tumour lysis. Soon after, it was shown that a direct injection is not necessary, and that tumour colonization was readily obtained after intravenous administration of spores[18]).
In CDEPT, a prodrug-converting enzyme expressed by a clostridial expression plasmid converts a prodrug into an active drug form within the tumor. While the prodrug is the inactive form and can be administrated to the blood, the products of the prodrug cleavage are highly cytotoxic and show their effect only in the vicinity of tumor cells.
Difficulties in the engineering of clostridial strains have restricted the application of other enzyme prodrug systems. So far, two enzymes have been applied in CDEPT: cytosine deaminase and nitroreductase.[19]
References
[edit]- ^ Karjoo, Zahra; Chen, Xuguang; Hatefi, Arash (2015-05-22). "Progress and problems with the use of suicide genes for targeted cancer therapy". Advanced Drug Delivery Reviews. 99 (Pt A): 113–28. doi:10.1016/j.addr.2015.05.009. ISSN 1872-8294. PMC 4758904. PMID 26004498.
- ^ Zawilska, JB; Wojcieszak, J; Olejniczak, AB (2013). "Prodrugs: A challenge for the drug development". Pharmacological Reports. 65 (1): 1–14. doi:10.1016/s1734-1140(13)70959-9. PMID 23563019.
- ^ Schellmann, N; Deckert, PM; Bachran, D; Fuchs, H; Bachran, C (September 2010). "Targeted enzyme prodrug therapies". Mini Reviews in Medicinal Chemistry. 10 (10): 887–904. doi:10.2174/138955710792007196. PMID 20560876.
- ^ Bagshawe KD (October 2006). "Antibody-directed enzyme prodrug therapy (ADEPT) for cancer". Expert Rev Anticancer Ther. 6 (10): 1421–31. doi:10.1586/14737140.6.10.1421. PMID 17069527. S2CID 2749415.
- ^ Bagshawe KD, Sharma SK, Springer CJ, Antoniw P (1995). "Antibody directed enzyme prodrug therapy (ADEPT): a pilot scale clinical trial". Tumor Targeting. 1: 17–29.
- ^ Bagshawe KD, Sharma SK (December 1996). "Cyclosporine delays host immune response to antibody enzyme conjugate in ADEPT". Transplant. Proc. 28 (6): 3156–8. PMID 8962223.
- ^ Ledermann JA, Begent RH, Bagshawe KD (November 1988). "Cyclosporin A prevents the anti-murine antibody response to a monoclonal anti-tumour antibody in rabbits". Br. J. Cancer. 58 (5): 562–6. doi:10.1038/bjc.1988.259. PMC 2246811. PMID 3265331.
- ^ KD Bagshawe and M Napier, Early clinical studies with ADEPT. In: RG Melton and RJ Knox Editors, Enzyme-Prodrug Strategies for Cancer Therapy Kluwer Academic, London (1999), 199–207.
- ^ Karjoo, Zahra; Chen, Xuguang; Hatefi, Arash (2015-05-22). "Progress and problems with the use of suicide genes for targeted cancer therapy". Advanced Drug Delivery Reviews. 99 (Pt A): 113–28. doi:10.1016/j.addr.2015.05.009. ISSN 1872-8294. PMC 4758904. PMID 26004498.
- ^ Robinson, Mark A.; Charlton, Stuart T.; Garnier, Philippe; Wang, Xiang-tao; Davis, Stanley S.; Perkins, Alan C.; Frier, Malcolm; Duncan, Ruth; Savage, Tony J. (2004-10-05). "LEAPT: Lectin-directed enzyme-activated prodrug therapy". Proceedings of the National Academy of Sciences of the United States of America. 101 (40): 14527–14532. Bibcode:2004PNAS..10114527R. doi:10.1073/pnas.0303574101. ISSN 0027-8424. PMC 521935. PMID 15448212.
- ^ Ан, иди; Браун, м (1 мая 2007 г.). «Нацеливание опухолей с гипоксией, активируемыми цитотоксинами» . Границы в биологии . 12 (8–12): 3483–501. doi : 10.2741/2329 . PMID 17485316 .
- ^ Schellmann, N; Deckert, PM; Бахран, D; Fuchs, h; Бахран, C (сентябрь 2010 г.). «Целевая фермент пролекарственная терапия». Мини -обзоры по лекарственной химии . 10 (10): 887–904. doi : 10.2174/138955710792007196 . PMID 20560876 .
- ^ Минтон, NP; Mauchline, ML; Леммон, MJ; Брем, JK; Фокс, м; Майкл, NP; Джаччия, а; Браун, JM (октябрь 1995). «Химиотерапевтическое нацеливание опухоли с использованием клостридиальных споров» . Обзоры микробиологии FEMS . 17 (3): 357–64. doi : 10.1111/j.1574-6976.1995.tb00219.x . PMID 7576773 .
- ^ Minton NP, Mauchline ML, Lemmon MJ, et al. (Октябрь 1995). «Химиотерапевтическое нацеливание опухоли с использованием клостридиальных споров» . FEMS Microbiol. Преподобный 17 (3): 357–64. doi : 10.1111/j.1574-6976.1995.tb00219.x . PMID 7576773 .
- ^ Nuyts S, Van Mellaert L, Hes J, Landuyt W, Lambin P, Anné J (февраль 2002 г.). «Споры Clostridium для доставки лекарств, специфичных для опухоли». Противоопухолевые препараты . 13 (2): 115–25. doi : 10.1097/00001813-200202000-00002 . PMID 11901303 .
- ^ Браун Дж. М., Уилсон В.Р. (июнь 2004 г.). «Использование гипоксии опухоли при лечении рака». НАТ Преподобный Рак . 4 (6): 437–47. doi : 10.1038/nrc1367 . PMID 15170446 . S2CID 3105010 .
- ^ Паркер Р.К., сантехник Х.К., Сибенманн Ко, Чепмен М.Г. (1947). «Влияние гистолитической инфекции и токсина на трансплантируемые опухоли мыши». Прокурор Соц Эксплуат Биол. Медик 66 (2): 461–5. doi : 10.3181/00379727-66-16124 . PMID 18921791 . S2CID 28348293 .
- ^ Malmgren RA, Flanigan CC (август 1955 г.). «Локализация вегетативной формы Tetani Clostridium в опухолях мыши после внутривенного введения споры» . Рак . 15 (7): 473–8. PMID 13240693 .
- ^ МИНТОН НП (декабрь 2003 г.). «Клостридиа в терапии рака». НАТ Rev. Microbiol . 1 (3): 237–42. doi : 10.1038/nrmicro777 . PMID 15035028 . S2CID 27737452 .