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Alternative Tumor-Targeting Strategies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In addition to drug delivery, the ClearPointTM system has been used in clinical trials for the delivery of gene therapies directly to brain tumors. For example, the Toca-511/Toca-FC treatment (vocimagene amiretrorepvec) is a combination of a replicating, non-lytic retroviral vector containing a gene encoding for the enzyme cytosine deaminase (CD) and a prodrug Toca FC, an extended-release formulation of the antifungal agent 5-fluorocytosine. The latter is a prodrug of 5-fluorouracil, a known anticancer agent that does not cross the blood–brain barrier whereas 5-fluorocytosine does. Used after a brain tumor has been removed, Toca-511 is injected into the tissues lining the cavity from which the tumor was removed using the ClearPointTM system. The virus replicates only in cells that are dividing such as any cancer cells left behind after the surgery, whereas healthy brain cells are either non-dividing or very slow dividing. The 5-fluorocytosine prodrug is then administered orally and, after crossing the blood–brain barrier and reaching the tumor site, is converted into the cytotoxic 5-fluorouracil in those dividing cells expressing cytosine deaminase. At the time of writing, the Toca-511/Toca-FC therapy is still in clinical trials.
3D Particles
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
Finally, Zhao et al. (2019) performed the simultaneous construction of a bifunctional particle with both targeting and catalytic function. To do this, they expressed the thermostable cytosine deaminase tagged with the Rev peptide at the N-terminus with each of the PP7-PP7-OVA1 and PP7-PP7-OVA2 VLP constructs. The resulting particles contained an average of 15−25 cytosine deaminase enzymes per particle.
Selective Drug Delivery Using Targeted Enzymes For Prodrug Activation
Published in Siegfried Matzku, Rolf A. Stahel, Antibodies in Diagnosis and Therapy, 2019
Nathan O. Siemers, Peter D. Senter
Another study of the utility of clearing agents in mAb–enzyme/prodrug therapy involved a mAb-cytosine deaminase conjugate that was capable of converting 5-fluorocytosine into 5-fluorouracil (Wallace et al, 1994). The mAb-cytosine deaminase conjugate contained the whole L6 mAb, and displayed very slow plasma clearance in mice with concomitant low tumor: blood ratios. Clearance of L6-cytosine deaminase was greatly accelerated by injecting an antibody against the L6 idiotype 24 h after conjugate administration. The blood levels of L6-cytosine deaminase dropped by a factor of 40-70, while the tumor levels were mostly maintained. As a result, very high doses of 5-fluorocytosine could be administered without any apparent toxicity. This led to vastly greater intra-tumoral 5-fluorouracil concentrations than those obtained in animals receiving systemic 5-fluorouracil therapy (Figure 4a). The prodrug: drug ratio was very high in the blood, kidneys and livers of mice that received the L6-cytosine deaminase/anti-idiotype/5-fluorocytosine combination, while the reverse was true for the tumor. Importantly, the intratumoral 5-fluorouracil concentration in the conjugate treated mice was 17-25 fold higher than the normal tissues tested. Finally, much lower amounts of 5-fluorouracil were generated in a tumor model that was apparently L6 antigen negative compared to the antigen positive line.
The Roles of Tissue Rigidity and Its Underlying Mechanisms in Promoting Tumor Growth
Published in Cancer Investigation, 2020
Muhammad Asyaari Zakaria, Nor Fadilah Rajab, Eng Wee Chua, Gayathri Thevi Selvarajah, Siti Fathiah Masre
Engineered drugs are another approach taken to increase the specificity and efficacy of drugs on the tumor. A rigid tumor is known to become resistant toward certain drugs and it makes the therapy ineffective. Thus, an engineered drug developed by Liu and Zhao (201), known as cell-based system (mechanoresponsive cell system; MRCS), based on engineered mesenchymal stem cells (MSCs), able to deliver the drug once it encounters high rigid area. It was able to drive the cytosine deaminase (CD) expression which converts the inactive chemotherapy drug (5-fluorocytosine) into the active drug 5-fluorouracil (5-FU) once in the target tissue. The MRCS was proven to be able to attenuate tumor growth of human breast and lung cancer by using in vivo model. This engineered drug is a huge leap in treating cancer as it is not affecting healthy normal tissue, thus limiting the toxicity effect because the production of 5-FU only occurred in the rigid tumor. Briefly, these studies proved that targeting the components, pathways, or the stroma directly, aiming to reduce or restore increased tissue rigidity is an ideal alternative that can be developed as anticancer agents to treat cancer.
Prodrugs for targeted cancer therapy
Published in Expert Review of Anticancer Therapy, 2019
Carla Souza, Diogo Silva Pellosi, Antonio Claudio Tedesco
The combination of bacterial cytosine deaminase and 5-fluorocytosine (5-FC) is a commonly used enzyme/prodrug system, which has been tested for the treatment of colorectal, breast, and head and neck solid tumors [2]. The conversion of 5-FC to the potent anticancer agent 5-fluorouracil (5-FU) occurs within the cells, preceded by the introduction of a cytosine deaminase (CD) gene of the Escherichia coli bacteria into cancer cells [3]. The CD/5-FC system is more advantageous than HSVTK/GCV due to the induction of a significant distant bystander effect. However, once 5-FC is transformed into 5-FU by normal flora in the gut, the clinical use of CD/5-FC is limited, as it may result in side effects. Currently, only one clinical trial is underway (NCT01562626). Additionally, some studies have demonstrated the significant advantages of using CD along with HSVTK/GCV, or as a radiation sensitizer in combination with radiotherapy [110]. 5-FC have also been encapsulated with bovine serum albumin (BSA) nanoparticles in order to improve its therapeutic efficacy and solubility, which suggests that GDEPT therapy could also be improved by utilizing nanoparticles technology to prepare prodrugs [111,112].
Early clinical trials of Toca 511 and Toca FC show a promising novel treatment for recurrent malignant glioma
Published in Expert Opinion on Investigational Drugs, 2019
Brandon D. Philbrick, D. Cory Adamson
Toca 511 (vocimagene amiretrorepvec) and 5-fluorocytosine (6-amino-5-fluoro-1H-pyrimidin-2-one) is an exciting new two-drug combination therapy under development. This enzyme/prodrug combination therapy is being investigated for its ability to treat rHGG. Toca 511 is a retroviral replicating vector based on a modified murine leukemia virus (MLV). It contains a transgene for modified yeast cytosine deaminase (CD) to promote genomic stability and increased enzyme specific activity compared to native yeast CD (Figure 1). This transgene has shown considerable genomic stability in in vivo studies. As an MLV, Toca 511 is only able to infect actively dividing cells, thus giving the virus tumor selectivity [16]. There are other established mechanisms imparting tumor selectivity, including defective innate immune signaling pathways in cancer cells [17], as well as suppression of adaptive immunity in the tumor microenvironment [18]. 5-fluorocytosine (Toca FC [5-FC is the immediate release, research grade agent) is an FDA approved drug for the treatment of fungal infections, but has potential to be effective against certain malignancies upon its conversion to 5-fluorouracil (5-FU), a known drug for cancers of the head and neck, GI, and breast [19–21]. 5-FU has been demonstrated to cross the blood-brain barrier, but Toca FC can more readily cross it within minutes of oral administration. Upon infection of HGG cells with Toca 511, CD is expressed and will actively convert Toca FC delivered to the tumor site into 5-FU. The cytotoxic effects of 5-FU occur following its conversion to 5-fluoro-2ʹ-deoxyuridine-5ʹ-monophosphate (5-FdUMP). 5-FdUMP is an irreversible inhibitor of thymidylate synthase and inhibits DNA synthesis by deoxythymidine triphosphate deprivation and causes DNA strand breakage, leading to cell death (Figure 1(b)).