Metabolism and Metabolic Actions of 6-Methylpurine and 2-Fluoroadenine in Human Cells

Parker, William B.; Allan, Paula W.; Shaddix, Sue C.; Rose, Lucy M.; Speegle, Heath F; Gillespie, G. Yancey; Bennett, L. Lee

doi:10.1016/s0006-2952(98)00034-3

Cited by 100 publications

(100 citation statements)

References 28 publications

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“…28,45 Nevertheless, the data con- Gene Therapy firm that OAdV220 can effectively deliver the PNP gene expression cassette into tumors in vivo and that PNP expression is sustained over at least a 6-day period.…”

Section: In Vivo Expression Of Transgene By Oadv220mentioning

confidence: 99%

“…27 Moreover, the purine metabolites can diffuse readily both between and within prostate epithelial cells creating an efficient bystander effect. [27][28][29] We have shown that PNP-GDEPT works well against human AI PC-3 prostate cancer cells grown in vitro 30 or subcutaneously (s.c.) in nude mice. 18 A recombinant human adenovirus (Ad5) containing the PNP gene controlled by the prostate-specific PSA promoter, together with the prodrug, 6-methyl-9-(2-deoxy-␤-D-erythro-pentofuranosyl) purine (6MEPDR, which is converted by PNP to 6 methylpurine, 6MEP) caused a 75% reduction in PC3 tumor growth, with a complete cure in 25% of mice, and significantly prolonged mouse survival, compared with a control virus that did not contain the active gene cassette.…”

Section: Introductionmentioning

confidence: 99%

“…Fludarabine has a Km for PNP which is approximately 1000-higher than that for 6MEPDR, but of the PNP metabolites, 2-fluoroadenine (2FA) is approximately 100-fold more potent as a growth inhibitor than 6MEP. 28 Moreover, 6MEPDR needs to be chemically synthesized for use, whereas fludarabine phosphate is available commercially. For this reason, our in vivo experiments were confined to the use of fludarabine phosphate.…”

Section: Introductionmentioning

confidence: 99%

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Gene therapy for prostate cancer delivered by ovine adenovirus and mediated by purine nucleoside phosphorylase and fludarabine in mouse models

et al. 2002

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Section: In Vivo Expression Of Transgene By Oadv220mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Gene therapy for prostate cancer delivered by ovine adenovirus and mediated by purine nucleoside phosphorylase and fludarabine in mouse models

et al. 2002

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“…Thus, cycling and nonproliferating cells are killed, primarily by inhibition of protein and RNA synthesis. 14 2-FA is also a more potent (B100-fold) cell growth inhibitor than 6-methylpurine (6MP). 4,14 The advantages of PNP-GDEPT are first, that the treatment can kill cells independently of proliferation; 14 for CaP, as few as 2% of cells may be in s phase.…”

Section: Introductionmentioning

confidence: 99%

Preclinical evaluation of a prostate-targeted gene-directed enzyme prodrug therapy delivered by ovine atadenovirus

et al. 2004

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Gene-directed enzyme prodrug therapy (GDEPT) based on the Escherichia coli enzyme, purine nucleoside phosphorylase (PNP), provides a novel strategy for treating slowly growing tumors like prostate cancer (CaP). PNP converts systemically administered prodrug, fludarabine phosphate, to a toxic metabolite, 2-fluoroadenine, that kills PNP-expressing and nearby cells by inhibiting DNA, RNA and protein synthesis. Reporter gene expression directed by a hybrid prostatedirected promoter and enhancer, PSMEPb, was assayed after plasmid transfection or viral transduction of prostate and nonCaP cell lines. Androgen-sensitive (AS) LNCaP-LN3 and androgen-independent (AI) PC3 human CaP xenografts in nude mice were injected intratumorally with an ovine atadenovirus vector, OAdV623, that carries the PNP gene under PSMEPb, formulated with cationic lipid for enhanced infectivity. Fludarabine phosphate was then given intraperitoneally for 5 days at 75 mg/m 2 /day. PNP expression was evaluated by enzymic conversion of its substrate using reverse phase HPLC. OAdV623 showed excellent in vitro transcriptional specificity for CaP cells. In vivo, expression of PNP persisted for 46 days after OAdV623 injection and a single treatment provided 100% increase in tumor doubling time and 450% inhibition of tumor growth for both LNCaP-LN3 and PC3 lines, with increased tumor necrosis and apoptosis and decreased tumor cell proliferation. OAdV623 significantly suppressed the growth of AS and AI human CaP xenografts in mice.

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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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Metabolism and Metabolic Actions of 6-Methylpurine and 2-Fluoroadenine in Human Cells

Cited by 100 publications

References 28 publications

Gene therapy for prostate cancer delivered by ovine adenovirus and mediated by purine nucleoside phosphorylase and fludarabine in mouse models

Gene therapy for prostate cancer delivered by ovine adenovirus and mediated by purine nucleoside phosphorylase and fludarabine in mouse models

Preclinical evaluation of a prostate-targeted gene-directed enzyme prodrug therapy delivered by ovine atadenovirus

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

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