Acute Toxicology and Pharmacokinetic Assessment of a Ribozyme (ANGIOZYME™) Targeting Vascular Endothelial Growth Factor Receptor mRNA in the Cynomolgus Monkey

Sandberg, Jennifer A.; Sproul, Christopher D.; Blanchard, Karin S.; Bellon, Laurent; Sweedler, David; Powell, James A.; Caputo, Florence A.; Kornbrust, Douglas J.; Parker, Vann P.; Parry, Tom J.; Blatt, Lawrence M.

doi:10.1089/oli.1.2000.10.153

Cited by 31 publications

(16 citation statements)

References 14 publications

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“…[80][81][82] Extensive pre-clinical studies in mice and monkeys have demonstrated no significant toxicities of angiozyme. 83,84 Angiozyme has been well tolerated by humans in phase I clinical studies, and has been evaluated in phase II trials in advanced and/or metastatic cancer patients alone or in combination with traditional chemotherapy. [85][86][87] However, regardless of the phase II trial results, the company has announced that it does not intend to develop angiozyme independently.…”

Section: B Agents Acting On the Receptor Of The Angiogenic Factormentioning

confidence: 99%

Anti‐angiogenic drugs: from bench to clinical trials

Quesada

Muñoz‐Chápuli

Medina

2006

Medicinal Research Reviews

142

126

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Angiogenesis, the generation of new capillaries through a process of pre-existing microvessel sprouting, is under stringent control and normally occurs only during embryonic and post-embryonic development, reproductive cycle, and wound repair. However, in many pathological conditions (solid tumor progression, metastasis, diabetic retinopathy, hemangioma, arthritis, psoriasis and atherosclerosis among others), the disease appears to be associated with persistent upregulated angiogenesis. The development of specific anti-angiogenic agents arises as an attractive therapeutic approach for the treatment of cancer and other angiogenesis-dependent diseases. The formation of new blood vessels is a complex multi-step process. Endothelial cells resting in the parent vessels are activated by an angiogenic signal and stimulated to synthesize and release degradative enzymes allowing endothelial cells to migrate, proliferate and finally differentiate to give rise to capillary tubules. Any of these steps may be a potential target for pharmacological intervention. In spite of the disappointing results obtained initially in clinical trials with anti-angiogenic drugs, recent reports with positive results in phases II and III trials encourage expectations in their therapeutic potential. This review discusses the current approaches for the discovery of new compounds that inhibit angiogenesis, with emphasis on the clinical developmental status of anti-angiogenic drugs.

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Section: B Agents Acting On the Receptor Of The Angiogenic Factormentioning

confidence: 99%

Anti‐angiogenic drugs: from bench to clinical trials

Quesada

Muñoz‐Chápuli

Medina

2006

Medicinal Research Reviews

142

126

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“…The typical dose required for efficacy ranges from 30 to 100 mg/m 2 . Hence, the downregulation of Flt-1 does not appear to cause any specific toxicity in the systems tested (23). Among the minor effects noted in a 28-day monkey study, kidney and liver cells accumulated basophilic granules, probably as a result of drug accumulation in these tissues.…”

Section: Figurementioning

confidence: 78%

Nuclease-resistant synthetic ribozymes: developing a new class of therapeutics

Usman¹,

Blatt²

2000

J. Clin. Invest.

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125

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The discovery of ribozymes by Cech and Altman has fundamentally changed the view of the function of RNA in chemistry, biology, and medicine (1-3). Prior to this discovery, RNA had been viewed as a passive molecule that only carried information or provided structure to RNA-protein complexes. It is now clear that RNA can act as an enzyme and is capable of catalyzing RNA splicing and cleavage, as well as several other chemical reactions. These novel activities of RNA now permit the development of enzymatic RNA molecules as therapeutic agents that can suppress the expression of deleterious proteins by catalyzing the trans-cleavage of the corresponding mRNAs (4). RNA targets for ribozyme-based therapeutics may encode oncoproteins, growth factors, proinflammatory cytokines and their corresponding cell-surface receptors, and signal transduction molecules; viral and microbial mRNAs or genomic RNAs are also readily cleaved by this approach.RNA-cleaving ribozymes gain their target specificity from Watson-Crick base-pairing between the ribozyme's binding-arm sequences and sequences that flank the cleavage site of the target RNA. Once bound, their mechanism of cleavage involves attack of the 2′-OH that is 5′ to the scissile bond in the target, thus destabilizing the target RNA's phosphate backbone. Upon cleavage, the resultant products dissociate from the ribozyme complex and the ribozyme is released and may bind and cleave other targets again. The cleavage event renders the mRNA untranslatable and leads to further degradation of the target by cellular ribonucleases.With the recent completion of the sequencing of the human genome and several viral and bacterial pathogens, the number of potential ribozyme drug targets is enormous. This number will increase as the functions of all the genes in the human genome become clearer and the number of pathogens being sequenced increases. However, if they are to reach the clinic, ribozymes directed at these targets will need to be designed so that they can survive in nuclease-rich biological tissues and fluids, have a favorable pharmacokinetic (PK) profile, and prove effective in preclinical cell culture and animal models.Several groups have demonstrated the efficacy of ribozymes in cell culture and animal models. To date, only three ribozymes -one vector-expressed and two synthetic -have been reported in clinical trials. The first, a retrovirally expressed ribozyme that targets the HIV tat and rev exons, entered clinical testing in late 1996 and is currently in phase II testing for patients with AIDS-related lymphoma. The second, ANGIOZYME, is directed against the mRNA for Flt-1 (VEGF-R1), the high-affinity receptor for VEGF. This antiangiogenic ribozyme entered phase I trials in late 1998, phase I/II trials in late 1999, and is currently in phase II trials for several tumor types. The third, HEP-TAZYME, a ribozyme targeting the 5′-untranslated region (5′-UTR) of the hepatitis C virus (HCV) RNA genome, has recently completed a phase I/II clinical trial in patients with chronic hepatit...

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“…Plasma samples obtained from animals treated with a single subcutaneous bolus injection of 48 or 118 mg/kg of RPI.13919 were used to compare the plasma concentrations of RPI.13919 obtained using either the DEAE/HPLC or the DEAE/C2-Empore/dialysis/CGE protocols and a phenol/chloroform /isoamyl alcohol extraction procedure previously described (27), followed by IEX-HPLC. Table 5 summarizes the observed plasma concentrations of RPI.13919 obtained by the different methods.…”

Section: Dosed Sample Analysismentioning

confidence: 99%