A phase I study of antisense oligonucleotide GTI-2040 given by continuous intravenous infusion in patients with advanced solid tumors

Desai, Anjali; Schilsky, Richard L.; Young, Aiping; Janisch, Linda; Stadler, Walter M.; Vogelzang, N. J.; Cadden, S.; Wright, Jim A.; Ratain, Mark J.

doi:10.1093/annonc/mdi178

Cited by 53 publications

(41 citation statements)

References 15 publications

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“…The starting dose of GTI-2040 was selected to be approximately 80% of the total dose of GTI-2040 administered safely during single agent solid tumor phase I studies (19). GTI-2040 infusion was followed by initiation of HiDAC to induce down-regulation of RNR before AraC exposure.…”

Section: Methodsmentioning

confidence: 99%

Phase I Study of GTI-2040, an Antisense to Ribonucleotide Reductase, in Combination with High-Dose Cytarabine in Patients with Acute Myeloid Leukemia

Klisovic¹,

Blum

Wei

et al. 2008

Clinical Cancer Research

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Purpose: Inhibition of ribonucleotide reductase reduces the availability of the endogenous pool of deoxycytidine and may increase cytarabine (AraC) cytotoxicity. We performed a phase I dose escalation trial of AraC combined with GTI-2040, a 20-mer antisense oligonucleotide shown in preclinical studies to decrease levels of the R2 subunit of ribonucleotide reductase, to determine the maximum tolerated dose in adults with relapsed/refractory acute myeloid leukemia. Experimental Design: Twenty-three adults (ages 18-59 years) were enrolled in this dose escalation phase I trial, receiving high-dose AraC twice daily combined with infusional GTI-2040. An ELISA-based assay measured plasma and intracellular concentrations of GTI-2040. R2 protein changes were evaluated by immunoblotting in pretreatment and posttreatment bone marrow samples. Results: The maximum tolerated dose was 5 mg/kg/d GTI-2040 (days 1-6) and 3 g/m 2 /dose AraC every 12 hours for 8 doses. Neurotoxicity was dose limiting. Eight patients (35%) achieved complete remission. Mean bone marrow intracellular concentration of GTI-2040 were higher at 120 hours than at 24 hours from the start of GTI-2040 (P = 0.002), suggesting intracellular drug accumulation over time. Reductions in bone marrow levels of R2 protein (>50%) were observed at 24 and 120 hours. Higher baseline R2 protein expression (P = 0.03) and reductions after 24 hours of GTI-2040 (P = 0.04) were associated with complete remission. Conclusions: GTI-2040 and high-dose AraC were coadministered safely with successful reduction of the intended R2 target and encouraging clinical results. The clinical efficacy of this combination will be tested in an upcoming phase II study.Nucleoside analogues constitute the backbone of several primary and salvage chemotherapy regimens for acute myeloid leukemia (AML; refs. 1, 2). By mimicking endogenous nucleosides, these compounds are incorporated into newly synthesized DNA and induce inhibition and chain termination of newly synthesized nucleic acid, thereby leading to apoptosis (3). Among pyrimidine analogues, cytarabine (AraC) differs from the endogenous cytidine counterpart by the presence of an arabinoside rather than a ribose sugar. This compound undergoes enzymatic phosphorylation into the active metabolite Ara-CTP before being incorporated in newly synthesized DNA. A direct correlation between intracellular levels of Ara-CTP and antileukemic effect has been identified, and different strategies to increase levels of the active metabolite have been investigated (4 -7).Inhibition of the ribonucleotide reductase (RNR) has the potential to increase AraC cytotoxicity. Composed of two subunits, R1 and R2, RNR is required for the reductive conversion of ribonucleotides to deoxynucleotides, a crucial rate-limiting step during DNA synthesis and repair (8, 9). Overexpression of RNR, commonly found in malignant cells, increases the endogenous pool of deoxynucleoside triphosphates, a potential mechanism of chemoresistance to nucleoside analogues competing for DN...

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Section: Methodsmentioning

confidence: 99%

Phase I Study of GTI-2040, an Antisense to Ribonucleotide Reductase, in Combination with High-Dose Cytarabine in Patients with Acute Myeloid Leukemia

Klisovic¹,

Blum

Wei

et al. 2008

Clinical Cancer Research

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“…The concept of using RRM2 mRNA inhibition as an anticancer strategy in humans is being tested by workers at Lorus Therapeutics (9). The results of a phase I trial of GTI-2040 given in patients with advanced solid tumors showed a manageable toxicity profile, and that it was generally well tolerated (10), leading to a phase I/II trial, in which GTI-2040 is given in combination with capecitabine to patients with metastatic renal cell carcinoma (11).…”

mentioning

confidence: 99%

Potent siRNA Inhibitors of Ribonucleotide Reductase Subunit RRM2 Reduce Cell Proliferation In vitro and In vivo

Heidel

Liu

Yen

et al. 2007

Clinical Cancer Research

145

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Purpose: Ribonucleotide reductase (RR) is a therapeutic target for DNA replication^dependent diseases such as cancer. Here, a potent small interfering RNA (siRNA) duplex against the M2 subunit of RR (RRM2) is developed and shown to reduce the growth potential of cancer cells both in vitro and in vivo. Experimental Design: Three anti-RRM2 siRNAs were identified via computational methods, and the potency of these and additional ''tiling'' duplexes was analyzed in cultured cells via cotransfections using a RRM2-luciferase fusion construct. Knockdown of RRM2 by the best duplex candidates was confirmed directly by Western blotting. The effect of potent duplexes on cell growth was investigated by a real-time cell electronic sensing assay. Finally, duplex performance was tested in vivo in luciferase-expressing cells via whole animal bioluminescence imaging. Results: Moderate anti-RRM2 effects are observed from the three duplexes identified by computational methods. However, the tiling experiments yielded an extremely potent duplex (siR2B+5). This duplex achieves significant knockdown of RRM2 protein in cultured cells and has pronounced antiproliferative activity. S.c. tumors of cells that had been transfected with siR2B+5 preinjection grew slower than those of control cells. Conclusions: An anti-RRM2 siRNA duplex is identified that exhibits significant antiproliferative activity in cancer cells of varying human type and species (mouse, rat, monkey); these findings suggest that this duplex is a promising candidate for therapeutic development.Ribonucleotide reductase (RR) catalyzes the conversion of ribonucleoside 5 ¶-diphosphates into their corresponding 2 ¶-deoxyribonucleotides and is a rate-limiting step in the pathway for the production of 2 ¶-deoxyribonucleoside 5 ¶-triphosphates that are necessary for DNA replication. Human RR consists of two subunits, RRM1 and RRM2, and the expression of both proteins is required for enzymatic activity. RRM1 and RRM2 are encoded by different genes on separate chromosomes, and their mRNAs are differentially expressed throughout the cell cycle. The cellular RRM1 protein level is kept relatively stable through the entire cell cycle, whereas RRM2 is only expressed during the late G 1 /early S phase when DNA replication occurs (1).RR has long been an important target for controlling pathologies that depend on DNA replication. Inhibition of RR activity has been tested as potential therapy in anticancer, antiviral, antibacterial, and other antiparasitic settings. A recent review on RR inhibitors as anticancer agents has appeared (2). Numerous small-molecule inhibitors, such as hydroxyurea (approved for human use) and triapine (3), interact with subunit RRM2. These small molecules are not completely specific to the RRM2 protein, however, and work continues on the design of more specific and effective inhibitors (4).A recent approach to RR down-regulation involves the use of nucleic acid -based, gene-specific inhibition. Yen et al. (5) and Lee et al. (6) have shown that antisense...

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“…47,48,50 Once in the cells, their effects are transient and diluted at each cell division, 51 so repeated dosing is required to achieve long-term therapeutic effects. Unmodified siRNA molecules also have potential toxicities, 52,53 via three main mechanisms, ie, saturation of RNAi machinery and competition within the miRNA pathway, stimulation of the immune response, and off-target effects.…”

Section: Difficulties In Therapeutic Applicationmentioning

confidence: 99%

Nanoparticle-based delivery of small interfering RNA: challenges for cancer therapy

Gulino¹

2012

IJN

115

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During recent decades there have been remarkable advances and profound changes in cancer therapy. Many therapeutic strategies learned at the bench, including monoclonal antibodies and small molecule inhibitors, have been used at the bedside, leading to important successes. One of the most important advances in biology has been the discovery that small interfering RNA (siRNA) is able to regulate the expression of genes, by a phenomenon known as RNA interference (RNAi). RNAi is one of the most rapidly growing fields of research in biology and therapeutics. Much research effort has gone into the application of this new discovery in the treatment of various diseases, including cancer. However, even though these molecules may have potential and strong utility, some limitations make their clinical application difficult, including delivery problems, side effects due to off-target actions, disturbance of physiological functions of the cellular machinery involved in gene silencing, and induction of the innate immune response. Many researchers have attempted to overcome these limitations and to improve the safety of potential RNAi-based therapeutics. Nanoparticles, which are nanostructured entities with tunable size, shape, and surface, as well as biological behavior, provide an ideal opportunity to modify current treatment regimens in a substantial way. These nanoparticles could be designed to surmount one or more of the barriers encountered by siRNA. Nanoparticle drug formulations afford the chance to improve drug bioavailability, exploiting superior tissue permeability, payload protection, and the "stealth" features of these entities. The main aims of this review are: to explain the siRNA mechanism with regard to potential applications in siRNA-based cancer therapy; to discuss the possible usefulness of nanoparticlebased delivery of certain molecules for overcoming present therapeutic limitations; to review the ongoing relevant clinical research with its pitfalls and promises; and to evaluate critically future perspectives and challenges in siRNA-based cancer therapy.

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A phase I study of antisense oligonucleotide GTI-2040 given by continuous intravenous infusion in patients with advanced solid tumors

Abstract: The recommended dose of GTI-2040 given on this infusion schedule is 185 mg/m(2)/day. GTI-2040 appears to have a manageable toxicity profile and is generally well tolerated as a single agent.

Cited by 53 publications

References 15 publications

Phase I Study of GTI-2040, an Antisense to Ribonucleotide Reductase, in Combination with High-Dose Cytarabine in Patients with Acute Myeloid Leukemia

Phase I Study of GTI-2040, an Antisense to Ribonucleotide Reductase, in Combination with High-Dose Cytarabine in Patients with Acute Myeloid Leukemia

Potent siRNA Inhibitors of Ribonucleotide Reductase Subunit RRM2 Reduce Cell Proliferation In vitro and In vivo

Nanoparticle-based delivery of small interfering RNA: challenges for cancer therapy

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