aprinocarsen and Neoplasms

The currently available treatment of cancer patients is based on the use of cytotoxic drugs and/or of ionizing radiations, which have potent antitumor activity, but also cause clinically relevant side effects, since they affect cellular targets that are common to both cancer cells and normal proliferating cells. In the past 20 years, the discoveries on the molecular mechanisms of cancer development and progression have prompted the search for agents which are more selective for cancer cell molecular targets. The possibility of combining conventional cytotoxic drugs with novel agents that specifically interfere with key pathways controlling cancer cell survival, proliferation, invasion and/or metastatic spreading has generated a wide interest. This could be a promising therapeutic approach for several reasons. First, since the cellular targets for these agents and their mechanism(s) of action are different from those of cytotoxic drugs, it is possible for their combination with chemotherapy without cross-resistance. Second, alterations in the expression and/or the activity of genes that regulate mitogenic signals not only can directly cause perturbation of cell growth, but also may affect the sensitivity of cancer cells to conventional chemotherapy and radiotherapy. In this review, we will discuss the biologic bases of the combination of molecular targeted drugs with conventional medical cancer treatments and the available results of the first series of clinical trials in cancer patients.

Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Combined Modality Therapy; ErbB Receptors; Farnesyltranstransferase; Genes, bcl-2; Humans; Neoplasms; Oligodeoxyribonucleotides, Antisense; Oligonucleotides; Protein Kinase C; ras Proteins; Signal Transduction; Thionucleotides

As our understanding of tumorigenesis increases, interference with the various signaling pathways of tumor cells has become an attractive approach to arresting tumor cell growth and overcoming chemoresistance. Among many intracellular signaling proteins, protein kinase C (PKC) isoenzymes have been identified as possible targets to render tumor cells more susceptible to apoptosis and growth arrest. We review the known biology of the alpha-isoenzyme of PKC in different cancers to provide a rational approach for developing targeted therapies using PKC modulators, including aprinocarsen, an antisense oligonucleotide (ASO) against PKC-alpha.

Topics: Animals; Enzyme Inhibitors; Humans; Neoplasms; Oligodeoxyribonucleotides, Antisense; Protein Kinase C; Protein Kinase C-alpha; Thionucleotides

There is a potential role for antisense oligonucleotides in the treatment of disease. The principle of antisense technology is the sequence-specific binding of an antisense oligonucleotide to target mRNA, resulting in the prevention of gene translation. The specificity of hybridisation makes antisense treatment an attractive strategy to selectively modulate the expression of genes involved in the pathogenesis of diseases. One antisense drug has been approved for local treatment of cytomegalovirus-induced retinitis, and several antisense oligonucleotides are in clinical trials, including oligonucleotides that target the mRNA of BCL2, protein-kinase-C alpha, and RAF kinase. Antisense oligonucleotides are well tolerated and might have therapeutic activity. Here, we summarise treatment ideas in this field, summarise clinical trials that are being done, discuss the potential contribution of CpG motif-mediated effects, and look at promising molecular targets to treat human cancer with antisense oligonucleotides.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Design; Humans; In Vitro Techniques; Isoenzymes; Neoplasms; Oligodeoxyribonucleotides, Antisense; Oligonucleotides; Oligonucleotides, Antisense; Phosphorothioate Oligonucleotides; Protein Kinase C; Protein Kinase C-alpha; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Thionucleotides

ISIS-3521 is a 20-mer antisense phosphorothioate oligonucleotide PKCa expression inhibitor, under development by Isis (formerly in collaboration with Novartis) for the potential treatment of solid tumors that are refractory to, or recurrent with, standard treatment regimens [175741]. In November 1999, Novartis announced that it would end its codevelopment of ISIS-3521 [348221], [348222]. In August 2001, Eli Lilly in-licensed ISIS-3521 [420062]. In October 2000, phase III trials of ISIS-3521, in combination with carboplatin and paclitaxel, were initiated for the treatment of non-small cell lung cancer (NSCLC) [386128]. The FDA granted ISIS-3521 Fast Track review status for NSCLC in November 2000 [388930]. In April 2001, Bear Sterns & Co predicted US approval of ISIS-3521 in 2002 [411081]. In August 2001, Eli Lilly and Isis entered into a four-year strategic alliance that includes ISIS-3521. For the license of ISIS-3521, Isis will receive $25 million in upfront fees and will be reimbursed for remaining phase III development and registration costs [420062].

Topics: Animals; Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Neoplasms; Oligodeoxyribonucleotides, Antisense; Structure-Activity Relationship; Thionucleotides

Topics: Animals; Antineoplastic Agents; Crohn Disease; Gene Expression; Humans; Molecular Biology; Neoplasms; Oligodeoxyribonucleotides, Antisense; Oligonucleotides, Antisense; Protein Biosynthesis; Proto-Oncogene Proteins c-raf; RNA, Messenger; Thionucleotides; Transformation, Genetic; Vascular Diseases

Topics: Cyclic AMP-Dependent Protein Kinases; Genes, bcl-2; Genes, myb; Genes, ras; Humans; Neoplasms; Oligodeoxyribonucleotides, Antisense; Oligonucleotides, Antisense; Protein Kinase C; Proto-Oncogene Proteins c-raf; RNA, Messenger; Thionucleotides

Antisense oligonucleotides offer the promise of therapeutic effect with few toxic effects, by virtue of their high selectivity. Preclinical studies have provided evidence of antisense effects in vitro and in vivo, and phase I clinical trials have demonstrated safety, feasibility and activity of antisense oligonucleotides for the treatment of cancer. This review summarizes the status of development of three anticancer antisense oligonucleotides from ISIS Pharmaceuticals.

Topics: Animals; Blood Coagulation Disorders; Clinical Trials, Phase I as Topic; Complement Pathway, Alternative; Drug Administration Schedule; Drug Design; Drug Interactions; Fatigue; Feasibility Studies; Female; Fever; Forecasting; Genes, ras; Genetic Therapy; Humans; Isoenzymes; Liver; Macaca fascicularis; Male; Mice; Neoplasm Proteins; Neoplasms; Oligodeoxyribonucleotides, Antisense; Oligonucleotides, Antisense; Partial Thromboplastin Time; Phosphorothioate Oligonucleotides; Protein Kinase C; Protein Kinase C-alpha; Proto-Oncogene Proteins c-raf; Proto-Oncogene Proteins p21(ras); Safety; Thionucleotides; Thrombocytopenia; Treatment Outcome; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

To determine the maximum-tolerated dose (MTD) and pharmacologic behavior of ISIS 3521 (ISI 641A), an antisense phosphorothioate oligonucleotide to protein kinase C-alpha.. Thirty-six patients with advanced cancer received 99 cycles of ISIS 3521 (0.15 to 6.0 mg/kg/d) as a 2-hour intravenous infusion administered three times per week for 3 consecutive weeks and repeated every 4 weeks. Plasma and urine sampling was performed during the first week of treatment and subjected to capillary gel electrophoresis to determine full-length antisense oligonucleotide in addition to chain-shortened metabolites.. Drug-related toxicities included mild to moderate nausea, vomiting, fever, chills, and fatigue. Hematologic toxicity was limited to thrombocytopenia (grade 1, four patients; grade 2, one patient; grade 3, one patient). There was no relationship between dose, maximum concentration of the drug (C(max)), or area under the plasma concentration versus time curve (AUC) and coagulation times or complement levels. Dose escalation was discontinued because of the attainment of peak plasma concentrations, which approached that associated with complement activation in primates. Two patients with non-Hodgkin's lymphoma who completed 17 and nine cycles of therapy achieved complete responses. The pharmacokinetic profile of ISIS 3521 revealed a short elimination half-life (18 to 92 minutes), as well as a dose-dependent decrease in clearance and dose-dependent increases in C(max), AUC, and elimination half-life.. No dose-limiting toxicity of ISIS 3521 was identified, and clinical activity was observed. A short elimination half-life was identified, which suggests that alternate schedules with prolonged administration may be necessary for further clinical development.

Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Combined Modality Therapy; Dose-Response Relationship, Drug; Electrophoresis, Capillary; Female; Half-Life; Humans; Isoenzymes; Male; Middle Aged; Neoplasms; Oligodeoxyribonucleotides, Antisense; Protein Kinase C; Protein Kinase C-alpha; Thionucleotides; Tomography, X-Ray Computed

Topics: Animals; Antineoplastic Agents; Genetic Therapy; Humans; Neoplasms; Oligodeoxyribonucleotides, Antisense; Phosphorothioate Oligonucleotides; Proto-Oncogene Proteins c-bcl-2; RNA, Neoplasm; Thionucleotides

It is well known that the PKC family of enzymes is involved in the propagation of intracellular signals and is implicated in cancers, inflammatory processes, cardiovascular and endocrinological diseases. Relatively low isozyme specificity has largely limited the clinical use of PKC antagonists. The members of the PKC family differ from each other at the mRNA level and the selectivity of antisense compounds is distinguished by this feature. According to ISIS Pharmaceuticals Inc antisense compounds are highly selective inhibitors even within a family of closely-related genes [321211]. The use of these compounds could be invaluable as tools to discover the mechanisms and roles of specific PKC isozyme in normal and diseased tissues and could provide the information for better cancer treatments [226799]. The isozyme of PKC-alpha is believed to play an important role in the proliferation of several types of cancer cells [234471-323703]. Recently, ISIS Pharmaceuticals received a patent US-05885970, covering the antisense technique targeting human PKC-alpha for cancer therapy (US-0588970). In the past few years, several effective antisense oligonucleotides (AS ONs) targeting murine and human PKC-alpha isozymes have been developed and a series of positive results have been obtained in cell culture and in nude mice cancer transplantation [327453]. Phase I clinical trials have shown that relatively high doses were well tolerated with no obvious side-effects [226799]. Whether these AS ONs are beneficial to patients suffering from cancer, either alone or in combination with other chemotherapy drugs is still under evaluation in a clinical setting.

Topics: Animals; Biological Availability; Cancer Vaccines; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Genetic Therapy; Hematologic Diseases; Humans; Isoenzymes; Mice; Mice, Nude; Neoplasm Proteins; Neoplasms; Oligodeoxyribonucleotides, Antisense; Organ Size; Patents as Topic; Protein Kinase C; Protein Kinase C-alpha; Structure-Activity Relationship; Thionucleotides; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Topics: Animals; Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Enzyme Inhibitors; Humans; Isoenzymes; Neoplasms; Oligodeoxyribonucleotides, Antisense; Oligonucleotides, Antisense; Protein Kinase C; Protein Kinase C-alpha; RNA, Messenger; Thionucleotides

A 20-mer phosphorothioate oligodeoxynucleotide (ISIS 3521) designed to hybridize sequences in the 3'-untranslated region of human protein kinase C-alpha (PKC-alpha) mRNA has been shown to inhibit the expression of PKC-alpha in multiple human cell lines. In human bladder carcinoma (T-24) cells, inhibition of PKC-alpha was both concentration dependent and oligonucleotide sequence specific. ISIS 3521 had a IC50 of 50-100 nM for PKC-alpha mRNA reduction and was without effect on the expression of other members of the PKC family of genes (PKC-eta and zeta). Toxicity studies in mice revealed that the oligodeoxynucleotide was well tolerated at repeat doses of 100 mg/kg i.v. for up to 14 days, with no acute toxicity apparent. The oligodeoxynucleotide was found to also inhibit the growth of three different human tumor cell lines, the T-24 bladder, human lung carcinoma (A549), and Colo 205 colon carcinoma grown in nude mice. The inhibition was dose dependent with ID50 values for the growth inhibition between 0.06 and 0.6 mg/kg daily when given i.v., depending on the cell line examined. Three control phosphorothioate oligodeoxynucleotides not targeting human PKC-alpha were without effect on the growth of the tumors at doses as high as 6 mg/kg. Recovery of ISIS 3521 from tumor tissue and resolution by capillary gel electrophoresis revealed that 24 It after the final dose of oligodeoxynucleotide, intact, full-length 20-mer material was present as well as some apparent exonuclease degradation products (e.g., n-1 and n-2 mers). These studies demonstrate the in vivo antitumor effects of an antisense oligodeoxynucleotide targeting PKC-alpha and suggest that this compound may be of value as a chemotherapeutic agent in the treatment of human cancers.

Topics: Animals; Antineoplastic Agents; Base Sequence; Cell Division; Enzyme Inhibitors; Female; Humans; Isoenzymes; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Sequence Data; Neoplasm Transplantation; Neoplasms; Oligodeoxyribonucleotides, Antisense; Oligonucleotides, Antisense; Protein Kinase C; Protein Kinase C-alpha; Thionucleotides; Transplantation, Heterologous; Tumor Cells, Cultured