Pharmacokinetics of an anti—human immunodeficiency virus antisense oligodeoxynucleotide phosphorothioate (GEM 91) in HIV-infected subjects*

Zhang, Ruiwen; Yan, Jieming; Shahinian, Harout; Amin, Girish; Lü, Zhihong; Liu, Tiepu; Saag, Michael S.; Jiang, Zhiwei; Temsamani, Jamal; Martin, R. Russell; Schechter, Paul J.; Agrawal, Sudhir; Diasio, Robert B.

doi:10.1016/0009-9236(95)90071-3

Cited by 125 publications

(41 citation statements)

References 23 publications

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“…Still, the methods used in dierent studies are not suited for the systemic treatment of tumor-bearing animals or cancer patients. Antisense-based methods, which have been proven to inhibit the expression of certain critical cancer genes speci®cally, have already entered dierent clinical studies (Agrawal, 1996;Crooke et al, 1994;Zhang et al, 1995). The antisense drug Vitravene has now been approved for the treatment of patients with cytomegalovirus-induced retinitis (Crooke, 1998).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of human polo-like kinase activity by antisense oligonucleotides induces growth inhibition in cancer cells

et al. 2002

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A central role for polo-like kinases (PLK) in regulating several stages of mitotic progression has been born out in several species. Overexpression of PLK1 is observed in the majority of hitherto analysed human tumors. PLK1 overexpression is a negative prognostic factor in patients suering from non-small cell lung cancer, head and neck tumors, esophageal carcinomas and melanomas. In order to de®ne the role of PLK1 for mitotic progression of human cells and for neoplastic cell growth, phosphorothioate antisense oligonucleotides (ASOs) were tested to selectively downregulate PLK1 expression in MDA-MB-435 (breast cancer), HeLa S3 (cervical carcinoma) and A549 (non-small cell lung cancer) cells. ASOs were identi®ed which suppress PLK1 mRNA and protein in a dose-dependent and sequence-speci®c manner. This approach also led to reduced PLK1 serine/threonine kinase activity. Downregulation of cellular PLK1 levels in cancer cells altered cell cycle progression moderately with an elevated percentage (20 ± 30%) of cells in G 2 /M. Furthermore, cells with reduced PLK1 protein gained a rounded phenotype with multiple centrosomes. Moreover, ASO treatment resulted in potent antiproliferative eects in cell culture. Considerable antitumor activity was observed in vivo against A549 cells. This study suggests that antisense inhibitors targeted against PLK1 at well tolerated doses may be considered as a cancer therapeutic agent.

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Section: Discussionmentioning

confidence: 99%

Downregulation of human polo-like kinase activity by antisense oligonucleotides induces growth inhibition in cancer cells

et al. 2002

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“…Antisense oligonucleotides are being evaluated for their therapeutic potential for various diseases (37)(38)(39)(40)(41)(42). These agents achieve their effect by targeting mRNA with which they can hybridize and specifically block protein expression (37-39); thus, antisense oligos offer the possibility for a specific and rational drug design (38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

Antitumor activity and pharmacokinetics of a mixed-backbone antisense oligonucleotide targeted to the RIα subunit of protein kinase A after oral administration

Wang

Cai

Zeng

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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124

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Overexpression of the RI␣ subunit of cAMP-dependent protein kinase (PKA) has been demonstrated in various human cancers. PKA has been suggested as a potential target for cancer therapy. The goal of the present study was to evaluate an anti-PKA antisense oligonucleotide (mixed-backbone oligonucleotide) as a therapeutic approach to human cancer treatment. The identified oligonucleotide inhibited the growth of cell lines of human colon cancer (LS174T, DLD-1), leukemia (HL-60), breast cancer (MCF-7, MDA-MB-468), and lung cancer (A549) in a time-, concentration-, and sequence-dependent manner. In a dose-dependent manner, the oligonucleotide displayed in vivo antitumor activity in severe combined immunodeficient and nude mice bearing xenografts of human cancers of the colon (LS174T), breast (MDA-MB-468), and lung (A549). The routes of drug administration were intraperitoneal and oral. Synergistic effects were found when the antisense oligonucleotide was used in combination with the cancer chemotherapeutic agent cisplatin. The pharmacokinetics of the oligonucleotide after oral administration of 35 S-labeled oligonucleotide into tumor-bearing mice indicated an accumulation and retention of the oligonucleotide in tumor tissue. This study further provides a basis for clinical studies of the antisense oligonucleotide targeted to the RI␣ subunit of PKA (GEM 231) as a cancer therapeutic agent used alone or in combination with conventional chemotherapy.antisense therapy ͉ oral drug delivery ͉ breast cancer ͉ colon cancer ͉ lung cancer c AMP-dependent protein kinase (PKA) is involved in various cellular functions, including cell proliferation, gene induction, metabolism, secretion, and ion-channel regulation. PKA is composed of two catalytic (C) and two regulatory (R) subunits and has type-I and type-II isozymes, with different R subunits, termed RI and RII, interacting with an identical C subunit (1). Thus far, four isoforms of R subunits, RI␣, RI␤, RII␣, and RII␤, have been identified. Increased expression of the RI␣ subunit of PKA correlates with cell proliferation and neoplastic growth (2). Overexpression of the RI␣ subunit of PKA occurs in various human tumor tissues and cell lines including cancers of breast (3-5), ovary (6, 7), lung (8), and colon (9-11). Furthermore, overexpression of the RI␣ subunit of PKA correlates with malignancy and poor prognosis in cancer patients (5-7). In addition, the RI␣ subunit interacts with the cytochrome c oxidase subunit vb (12), which is involved in controlling multiple drug resistance (13,14), and is associated with tumor sensitivity to cancer chemotherapeutic agents such as cisplatin (15). PKA also phosphorylates the epidermal growth factor receptor and decreases its tyrosine kinase activity and signal transduction both in vitro and in vivo (16). Therefore, the RI␣ subunit of PKA is a potential target for human cancer therapy. In the last decade, there have been increasing efforts to develop PKA-specific inhibitors as cancer therapeutic agents (2, 17).Selective down-regulation of the...

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“…Despite the fact that the mechanism whereby these molecules modulate gene expression is not always certain, 9,55-57 clinical development of antisense compounds has proceeded to the point where several oligonucleotide drugs have entered phase I/II and, in a few cases, phase III trials. Reports of such trials in patients with advanced cancers [58][59][60][61][62][63] and human immunodeficiency virus (HIV) 64,65 have recently been published. Although the oligonucleotides' sequence and chemical backbones varied, all compounds were well tolerated.…”

Section: Discussionmentioning

confidence: 99%

Oligodeoxynucleotide-mediated inhibition of c-myb gene expression in autografted bone marrow: a pilot study

Luger

O’Brien

Ratajczak

et al. 2002

Blood

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Antisense oligodeoxynucleotide (ODN) drugs might be more effective if their delivery was optimized and they were targeted to short-lived proteins encoded by messenger RNA (mRNA) species with equally short half-lives. To test this hypothesis, an ODN targeted to the c-myb proto-oncogene was developed and used to purge marrow autografts administered to allograft-ineligible chronic myelogenous leukemia patients. CD34 ؉ marrow cells were purged with ODN for either 24 (n ‫؍‬ 19) or 72 (n ‫؍‬ 5) hours. After purging, Myb mRNA levels declined substantially in approximately 50% of patients. Analysis of bcr/abl expression in longterm culture-initiating cells suggested that purging had been accomplished at a primitive cell level in more than 50% of patients and was ODN dependent. Day-100 cytogenetics were evaluated in surviving patients who engrafted without infusion of unmanipulated "backup" marrow (n ‫؍‬ 14). Whereas all patients were approximately 100% Philadelphia chromosome-positive (Ph ؉ ) before transplantation, 2 patients had complete cytogenetic remissions; 3 patients had fewer than 33% Ph ؉ metaphases; and 8 remained 100% Ph ؉ . One patient's marrow yielded no metaphases, but fluorescent in situ hybridization evaluation approximately 18 months after transplantation revealed approximately 45% bcr/abl ؉ cells, suggesting that 6 of 14 patients had originally obtained a major cytogenetic response. Conclusions regarding clinical efficacy of ODN marrow purging cannot be drawn from this small pilot study. Nevertheless, these results lead to the speculation that enhanced delivery of ODN, targeted to critical proteins of short half-life, might lead to the development of more effective nucleic acid drugs and the enhanced clinical utility of these compounds in the future. (Blood. 2002;99:1150-1158

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Pharmacokinetics of an anti—human immunodeficiency virus antisense oligodeoxynucleotide phosphorothioate (GEM 91) in HIV-infected subjects*

Cited by 125 publications

References 23 publications

Downregulation of human polo-like kinase activity by antisense oligonucleotides induces growth inhibition in cancer cells

Downregulation of human polo-like kinase activity by antisense oligonucleotides induces growth inhibition in cancer cells

Antitumor activity and pharmacokinetics of a mixed-backbone antisense oligonucleotide targeted to the RIα subunit of protein kinase A after oral administration

Oligodeoxynucleotide-mediated inhibition of c-myb gene expression in autografted bone marrow: a pilot study

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