Progress and problems with the use of suicide genes for targeted cancer therapy

Karjoo, Zahra; Chen, Xuguang; Hatefi, Arash

doi:10.1016/j.addr.2015.05.009

Cited by 153 publications

(178 citation statements)

References 160 publications

(168 reference statements)

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“…Suicide genes are still an important tool for in vivo safety control in adoptive cellular immunotherapy with autologous or allogeneic T-cells genetically modified with chimeric antigen receptors or affinity-enhanced T-cell receptor chains (reviewed in Karjoo et al (2016)). The concept of using the human CYB4B1 as a suicide gene was developed by Wiek et al (2015) who showed that the exchange p.S427P (h-P427) is important for both protein stability as well as partially rescuing the catalytic activity of the human enzyme against 4-IPO 12.…”

Section: Introductionmentioning

confidence: 99%

Ligand characterization of CYP4B1 isoforms modified for high-level expression inEscherichia coliand HepG2 cells

Roellecke

Jäger

Gyurov

et al. 2017

Protein Engineering, Design and Selection

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Human CYP4B1, a cytochrome P450 monooxygenase predominantly expressed in the lung, inefficiently metabolizes classical CYP4B1 substrates, such as the naturally occurring furan pro-toxin 4-ipomeanol (4-IPO). Highly active animal forms of the enzyme convert 4-IPO to reactive alkylating metabolite(s) that bind(s) to cellular macromolecules. By substitution of 13 amino acids, we restored the enzymatic activity of human CYP4B1 toward 4-IPO and this modified cDNA is potentially valuable as a suicide gene for adoptive T-cell therapies. In order to find novel pro-toxins, we tested numerous furan analogs in in vitro cell culture cytotoxicity assays by expressing the wildtype rabbit and variants of human CYP4B1 in human liver-derived HepG2 cells. To evaluate the CYP4B1 substrate specificities and furan analog catalysis, we optimized the N-terminal sequence of the CYP4B1 variants by modification/truncation and established their heterologous expression in Escherichia coli (yielding 70 and 800 nmol·l −1 of recombinant human and rabbit enzyme, respectively). Finally, spectral binding affinities and oxidative metabolism of the furan analogs by the purified recombinant CYP4B1 variants were analyzed: the naturally occurring perilla ketone was found to be the tightest binder to CYP4B1, but also the analog that was most extensively metabolized by oxidative processes to numerous non-reactive reaction products.

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Section: Introductionmentioning

confidence: 99%

Ligand characterization of CYP4B1 isoforms modified for high-level expression inEscherichia coliand HepG2 cells

Roellecke

Jäger

Gyurov

et al. 2017

Protein Engineering, Design and Selection

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“…Tested drugs included MMAE (microtubule‐disrupting agent),12, 13 SN‐38 (topoisomerase I inhibitor),14 etoposide (topoisomerase II inhibitor),15 cisplatin (DNA crosslinker),16 6‐MP (nucleotide analogue and inhibitor of RNA and protein synthesis)17, 18 and 5‐FU (pyrimidine analogue and thymidine synthase inhibitor) 18, 19. As we mentioned above, OVASC‐1 cells have been shown to be resistant to paclitaxel; therefore, we did not examine their sensitivity to this drug at the in vitro level to avoid redundancy.…”

Section: Resultsmentioning

confidence: 99%

A novel chemotherapeutic protocol for peritoneal metastasis and inhibition of relapse in drug resistant ovarian cancer

et al. 2018

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The majority of ovarian cancer patients are diagnosed in late stages of the disease, in which the tumor cells have leaked into the peritoneum and are present as tumorspheres. These tumorspheres are rich in cancer stem‐like cells (CSCs), which are resistant to therapy and are a major source of relapse. The purpose of this research was to identify a safe therapeutic approach that could eradicate the peritoneal CSC‐rich tumorspheres and inhibit relapse. Highly metastatic ascitic cells (OVASC‐1) that are resistant to standard‐of‐care chemotherapy due to upregulation of MDR1 gene were obtained from a patient with ovarian carcinoma and recurrent disease. CSC‐rich tumorspheres were generated, characterized, and treated with different chemotherapeutics. The most effective drug combination that could eradicate tumorspheres at nanomolar levels despite upregulation of MDR1 gene was identified. Luciferase‐expressing OVASC‐1 cells were implanted in the peritoneum of nude mice and treated with the identified drug combination. The progression of disease, response to therapy and recurrence were studied by quantitative imaging. Toxicity to abdominal tissues was studied by histopathology. Mice implanted with intraperitoneal (IP) OVASC‐1 xenografts showed limited response to combination therapy with cisplatin/paclitaxel at the maximum tolerated dose. Despite overexpression of MDR1 on OVASC‐1 cells, mice treated with our combination IP low‐dose MMAE and SN‐38 chemotherapy showed complete response without relapse. No signs of toxicity to abdominal tissues were observed. While MMAE and SN‐38 are not administered as free drugs due to their high potency and potential for systemic toxicity, our low‐dose localized therapy approach effectively restricted the cytotoxic effects to the tumor cells in the peritoneum. Consequently, maximum efficacy with minimal adverse effects was achieved. These remarkable results with IP low‐dose combination chemotherapy encourage investigation into its potential clinical application as either first‐line therapy or in cases of acquired resistance to cisplatin and paclitaxel.

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“…While past clinical trials with CD/5-FC system alone have reported limited success (Karjoo et al 2016), there are several new clinical trials in progress which could produce interesting outcomes. For instance in one trial, genetically-modified neural stem cells expressing bCD are used in combination with orally administered 5-FC for the treatment of recurrent gliomas (NCT01172964).…”

Section: Enzyme/prodrug Systemsmentioning

confidence: 99%

Enzyme/Prodrug Systems for Cancer Gene Therapy

et al. 2016

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The use of enzyme/prodrug system has gained attention because it could help improve the efficacy and safety of conventional cancer chemotherapies. In this approach, cancer cells are first transfected with a gene that can express an enzyme with ability to convert a non-toxic prodrug into its active cytotoxic form. As a result, the activated prodrug could kill the transfected cancer cells. Despite the significant progress of different suicide gene therapy protocols in preclinical studies and early clinical trials, none has reached the clinic due to several shortcomings. These include slow prodrug-drug conversion rate, low transfection/transduction efficiency of the vectors and nonspecific toxicity/immunogenicity related to the delivery systems, plasmid DNA, enzymes and/or prodrugs. This mini review aims at providing an overview of the most widely used enzyme/prodrug systems with emphasis on reporting the results of the recent preclinical and clinical studies.

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Progress and problems with the use of suicide genes for targeted cancer therapy

Cited by 153 publications

References 160 publications

Ligand characterization of CYP4B1 isoforms modified for high-level expression inEscherichia coliand HepG2 cells

Ligand characterization of CYP4B1 isoforms modified for high-level expression inEscherichia coliand HepG2 cells

A novel chemotherapeutic protocol for peritoneal metastasis and inhibition of relapse in drug resistant ovarian cancer

Enzyme/Prodrug Systems for Cancer Gene Therapy

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