piperidines and tipifarnib

The tyrosine kinase inhibitors (TKIs) have revolutionized the management of chronic myeloid leukemia (CML) and BCR-ABL1 inhibitors form the mainstay of CML treatment. Although patients with CML generally do well under TKI therapy, there is a subgroup of patients who are resistant and/or intolerant to TKIs. In these group of patients, there is the need of additional treatment strategies. In this review, we provide an update on the current knowledge of these novel treatment approaches that can be used alone and/or in combination with TKIs.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Drug Resistance, Neoplasm; Everolimus; Fusion Proteins, bcr-abl; Gene Expression; Histone Deacetylase Inhibitors; Homoharringtonine; Humans; Immunotherapy; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Molecular Targeted Therapy; Niacinamide; Piperidines; Polyethylene Glycols; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Quinolones; Recombinant Proteins

Farnesyltransferase inhibitors (FTIs) have mainly been used in cancer therapy. However, more recently, investigations on these inhibitors revealed that FTIs can be used for the treatment of other diseases such as Progeria, P. falciparum resistant malaria, Trypnosomatid, etc. Hence the development of novel FTIs is an important task for the drug discovery program. Initially, numerous peptidomimetic FTIs were developed from the template of CAAX (CVIM was the first pharmacophore model used as a peptidomimetic). Later, many non-peptidomimetic FTIs have been discovered with the structural modification of the peptidomimetics. The structural analysis of those developed FTIs by various researchers suggested that the presence of a heterocycle or a polar group in place of the thiol group is required for interaction with the Zn(2+) ion. The bulky naphthyl, quinolinyl, phenyl, phenothazine, etc in this position provide better hydrophobicity to the molecules which interact with the aromatic amino acid moieties in the hydrophobic pocket. A hydrophilic region with polar groups is necessary for the polar or hydrogen bonding interactions with the amino acids or water molecules in the active site. Many FTIs have been isolated from natural products, which possessed inhibitory activity against farnesyltransferase (FTase). Among them, pepticinnamin E (9R), fusidienol (9T), gliotoxin (9V), cylindrol A (9X), etc possessed potential FTase inhibitory activities and their structural features are comparable to those of the synthetic molecules. The clinical studies progressing on FTIs showed that tipifarnib in combination with bortezomib is used for the treatment of patients with advanced acute leukemias. Successful phase I and II studies are undergoing for tipifarnib alone or in combination with other drugs/radiation for the treatment of multiple myeloma, AML, breast cancer, mantle cell lymphoma, solid tumors, non-small cell lung cancer (NSCLC), pancreatic cancer, glioblastoma, etc. Phase I pharmacokinetic (maximum tolerated dose, toxicity) and pharmacodynamic studies of AZD3409 (an orally active double prodrug) is progressing on patients with solid malignancies taking 500 mg once a day. A phase II study is undergoing on lonafarnib alone and in combination with zoledronic acid and pravastatin for the treatment of Hutchinson-Gilford Progeria syndrome (HGPS) and progeroid laminopathies. Lonafarnib therapy improved cardiovascular status of children with HGPS, by improved peripheral art

Topics: Antineoplastic Agents; Biological Products; Clinical Trials as Topic; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Neoplasms; Piperidines; Pyridines; Quantitative Structure-Activity Relationship; Quinolones

Farnesyltransferase inhibitors (FTIs) inhibit certain cellular signal transduction pathways, and are being evaluated for activity in hematologic malignancies. Tipifarnib and lonafarnib are orally available FTIs that are active against a variety of targets and inhibit several pathways involved in the pathogenesis of hematologic malignancies. FTIs have demonstrated activity in a variety of hematologic diseases, including acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia, and multiple myeloma. This article reviews the clinical experience with tipifarnib and lonafarnib in the treatment of hematologic malignancies.

Topics: Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Enzyme Inhibitors; Farnesyltranstransferase; Hematologic Neoplasms; Humans; Piperidines; Pyridines; Quinolones; Signal Transduction

The farnesyltransferase inhibitors (FTIs) are in active clinical development in a variety of human malignancies. The most promising activity to date has been demonstrated in patients with hematologic malignancies, in particular acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). In patients with MDS, two nonpeptidomimetic agents, tipifarnib (Zarnestra, Johnson & Johnson, New Brunswick, NJ) and lonafarnib (Sarasar, Schering-Plough, Kenilworth, NJ) have been the most extensively studied. In both phase I and phase II trials, tipifarnib has demonstrated significant efficacy, with overall response rates of 30% and complete remissions in about 15%. Dose-limiting adverse effects have been primarily myelosuppression, although fatigue, neurotoxicity, and occasional renal dysfunction have required dose reductions. Lonafarnib in patients with MDS has also resulted in clinical responses in approximately 30%, including significant improvements in platelet counts. Lonafarnib has been associated primarily with diarrhea and other gastrointestinal toxicity, anorexia, and nausea, which has limited its efficacy. Clinical response correlation with documentation of inhibition of farnesyltransferase and/or evidence of decreased farnesylation of downstream protein targets has not been demonstrated with either agent. In addition, the presence of an activating Ras mutation has not predicted response to therapy with FTIs in MDS and AML. Despite this lack of evidence, significant clinical efficacy of the FTIs has been observed in MDS, on a par with the efficacy of currently available chemotherapeutic agents, leading to further development of this new class of drugs in MDS and AML.

Topics: Adult; Aged; Antineoplastic Agents; Bone Marrow Diseases; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Disease Progression; Farnesyltranstransferase; Gastrointestinal Diseases; Genes, ras; Hematologic Neoplasms; Humans; Middle Aged; Myelodysplastic Syndromes; Piperidines; Prenylation; Protein Processing, Post-Translational; Pyridines; Quinolones; Treatment Outcome

The ras family of proto-oncogenes are upstream mediators of several essential cellular signal transduction pathways involved in cell proliferation and survival. Point mutations of ras oncogenes result in constitutive activation of oncogenic Ras. The key step in post-translational processing of Ras protein is farnesylation by farnesyl transferase. Inhibitors of this enzyme were developed initially as a therapeutic strategy for Ras-mutated tumors. Moreover, it is now clear that farnesyl transferase inhibitors (FTIs) have activity independent of Ras, and show some effects on tumors without oncogenic ras mutations. Preclinical data show that FTIs can inhibit proliferation of breast cancer cells in vitro and in vivo, and phase II studies of FTI-R115777 in advanced breast cancer show encouraging results. Therefore, FTIs, used alone or with other agents, may be a novel therapeutic approach for breast cancer.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Proliferation; Enzyme Inhibitors; Farnesyltranstransferase; Female; Genes, ras; Humans; Piperidines; Protein Prenylation; Pyridines; Quinolones; ras Proteins

Farnesyltransferase inhibitors (FTIs) are small-molecule inhibitors that selectivly inhibit farnesylation of a number of intracellular substrate proteins such as Ras. Preclinical work has revealed their ability to effectively inhibit tumor growth in vitro and in vivo in animal models across a wide range of malignant phenotypes. Acute myeloid leukemias (AMLs) are appropriate disease targets in that they express relevant biologic targets such as Ras, MEK, AKT, and others that may depend upon farnesyl protein transferase activity to promote cell proliferation and survival. Indeed, different intracellular proteins are substrates for prenylation. Interruption of prenylation may prevent substrates from undergoing maturation which may result in the inhibition of cellular events that depend on the function of those substrates. Phase I trials in AML and myelodysplasia have demonstrated biologic and clinical activities as determined by target enzyme inhibition, low toxicity, and both complete and partial responses. As a result, phase II trials have been initiated in order to further validate clinical activity and to identify downstream signal transduction targets that may be modified by these agents. It is anticipated that these studies will serve to define the optimal roles of FTIs in patients with these hematologic malignancies and provide insight into effective methods by which to combine FTIs with other agents.

Topics: Alkyl and Aryl Transferases; Benzodiazepines; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Resistance, Neoplasm; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Imidazoles; Leukemia, Myeloid, Acute; Mitogen-Activated Protein Kinase 1; Myeloproliferative Disorders; Piperidines; Protein Prenylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Pyridines; Quinolones; ras Proteins; rho GTP-Binding Proteins

Cell proliferation, differentiation, and survival are regulated by a number of extracellular hormones, growth factors, and cytokines in complex organisms. The transduction of the signals by these factors from the outside to the nucleus often requires the presence of small intracellular proteins (i.e. ras and other small G proteins) that are linked to the plasma membrane through a isoprenyl residue that functions as hydrophobic anchor. Isoprenylation is a complex process regulated by different enzymatic steps that could represent potential molecular targets for anti-cancer strategies. In the present paper the different transduction pathways regulated by some isoprenylated proteins such as ras and other small G proteins are described. Moreover, the molecular mechanisms of the isoprenylation process and the mode of action of the different isoprenylation inhibitors are discussed with attention to statins, farnesyltransferase inhibitors (FTI) and aminobisphosphonates. The role of different candidate targets in the determination of anti-tumour effects by FTIs is also described in order to define potential molecular markers predictor of clinical response. On the basis of several preclinical data, new strategies based on multi-step enzyme inhibition or on target prioritization are proposed in order to enhance the anti-tumour activity of agents inhibiting isoprenylation. Finally, a summary of the principal data on clinical trials based on the use of FTIs and statins is given. In conclusion, the inhibition of isoprenylation is an attractive, but still not completely investigated therapeutic alternative that requires optimization for the translation in the current treatment of neoplasms.

Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; Benzodiazepines; Farnesyltranstransferase; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Imidazoles; Mevalonic Acid; Neoplasms; Phosphatidylinositol 3-Kinases; Piperidines; Protein Prenylation; Protein Processing, Post-Translational; Pyridines; Quinolones; ras Proteins

The farnesyltransferase inhibitors (FTIs) are in active clinical development in a variety of human malignancies. The most promising activity to date has been demonstrated in patients with hematological malignancies, in particular acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). In patients with MDS, two non-peptidomimetic agents, tipifarnib (Zarnestra, Johnson & Johnson, New Brunswick, NJ) and lonafarnib (Sarasar, Schering-Plough, Kenilworth, NJ) have been the most extensively studied. In both phase I and phase II trials, tipifarnib has demonstrated significant efficacy with overall response rates of 30%, with complete remissions in about 15%. Dose-limiting side effects have been primarily myelosuppression, although fatigue, neurotoxicity, and occasional renal dysfunction have required dose reductions. Lonafarnib in patients with MDS has also resulted in clinical responses in approximately 30%, including significant improvements in platelet counts. Lonafarnib has been associated with primarily diarrhea and other gastrointestinal toxicity, anorexia, and nausea, which has limited its efficacy. Clinical response correlation with documentation of inhibition of farnesyltransferase and/or evidence of decreased farnesylation of downstream protein targets has not been demonstrated with either agent. In addition, the presence of an activating Ras mutation has not predicted response to therapy with FTIs in MDS and AML. Despite this, significant clinical efficacy of the FTIs in MDS, on par with that of currently available chemotherapeutic agents, has been observed, leading to further development of this new class of drugs in MDS and AML.

Topics: Acute Disease; Aged; Alkyl and Aryl Transferases; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Disease Progression; Enzyme Inhibitors; Farnesyltranstransferase; Genes, ras; Hematologic Neoplasms; Humans; Leukemia, Myeloid; Middle Aged; Myelodysplastic Syndromes; Piperidines; Protein Prenylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins p21(ras); Pyridines; Quinolones; Remission Induction; Signal Transduction; Treatment Outcome

Farnesyl transferase inhibitors are a new class of biologically active anticancer drugs. The exact mechanism of action of this class of agents is, however, currently unknown. The drugs inhibit farnesylation of a wide range of target proteins, including Ras. It is thought that these agents block Ras activation through inhibition of the enzyme farnesyl transferase, ultimately resulting in cell growth arrest. In preclinical models, the farnesyl transferase inhibitors showed great potency against tumor cells; yet in clinical studies, their activity was far less than anticipated. Reasons for this disappointing clinical outcome might be found in the drug-development process. In this paper, we outline an algorithm that is potentially useful for the development of biologically active anticancer drugs. The development of farnesyl transferase inhibitors, from discovery to clinical trials, is reviewed on the basis of this algorithm. We found that two important steps of this algorithm were underestimated. First, understanding of the molecular biology of the defective pathway has mainly been focused on H-Ras activation, whereas activation of K-Ras or other farnesylated proteins is probably more important in tumorigenesis. Inhibition of farnesylation is possibly not sufficient, because geranylgeranylation might activate K-Ras and suppress the effect of farnesyl transferase inhibitors. Furthermore, a well-defined proof of concept in preclinical and clinical studies has not been achieved. Integrating the proposed algorithm in future studies of newly developed biologically active anti-cancer drugs might increase the rate of success of these compounds in patients.

Topics: Animals; Antineoplastic Agents; Benzodiazepines; Clinical Trials as Topic; Drug Design; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Imidazoles; Piperidines; Pyridines; Quinolones; ras Proteins

Topics: Animals; Benzamides; Chromosome Aberrations; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Hematopoietic Stem Cell Transplantation; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Piperazines; Piperidines; Pyridines; Pyrimidines; Quinolones; Randomized Controlled Trials as Topic; Thionucleotides

Farnesyl transferase inhibitors (FTIs) are a novel class of anti-cancer agents that competitively inhibit farnesyl protein transferase (FTase). Initially developed to inhibit the prenylation necessary for Ras activation, their mechanism of action seems to be more complex, involving other proteins unrelated to Ras. FTIs have been developed and tested across a wide range of human cancers. At least 3 agents within this family have been investigated in hematologic malignancies. These are tipifarnib (R115777, Zarnestra), lonafarnib (SCH66336, Sarasar), both of which are orally administered, and BMS-214662, which is given intravenously. Preliminary results from clinical trials demonstrate enzyme target inhibition, a favorable toxicity profile and promising efficacy. Ongoing studies will better determine their mechanism of action and the role of combination with other agents, defining their place in the therapeutic arsenal of hematologic disorders.

Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Benzodiazepines; Cell Line, Tumor; Clinical Trials as Topic; Enzyme Inhibitors; Farnesyltranstransferase; Hematologic Neoplasms; Humans; Imidazoles; Piperidines; Pyridines; Quinolones; ras Proteins; Signal Transduction

Ras mutation is observed in 20-30% of human malignancies. Ras proteins belong to the family of G-proteins, which are able to bind and hydrolyze guanosine triphosphate reversibly. They are responsible for signal transduction within cell. Ras undergoes several steps of posttranslational modification, but only farmesylation is necessary for its biologic activity. The crucial enzyme of farnesylation - farnesyltransferase (FT-ase) has become a major target for the development of new anticancer agents--farnesyltransferase inhibitors (FTI). Mutation of Ras results in the abrogation of its normal GTP-ase activity and subsequently it causes a permanent activation of Ras with uncontrolled growth and proliferation of cells. Recently published trials revealed, that FTI are highly effective in several malignant disorders, including myeloid leukemias. FTI are bioavailable after oral administration and have an acceptable toxicity profile. No enhanced myelosuppression effect was noted. It was observed, that FTI may increase cytotoxic effect of some antineoplastic drugs and radiotherapy. It seems that these agents are an interesting and promising therapeutic option for patients, who were resistant to conventional chemotherapy. The benefits of ambulatory drug administration may improve the quality of life in oncological patients. The II phase trials with FTI are under way and we hope, that these agents will find an unquestionable position in treatment of patients with malignancies.

Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Farnesyltranstransferase; Genes, ras; GTP-Binding Proteins; Guanosine Triphosphate; Humans; Imidazoles; Neoplasms; Piperidines; Point Mutation; Pyridines; Quinolones; Signal Transduction

Farnesylation of Ras, a protooncogene that is frequently mutated in a number of malignancies, is critical for its biologic function. This observation has led to the development of several agents that inhibit farnesyltransferase, known as farnesyltransferase inhibitors (FTIs). The antiproliferative and antitumor effects of these agents have been demonstrated in preclinical and clinical studies. Interestingly, FTI activity does not necessarily rely on ras mutational status, indicating that Ras is not the only FTI target. Clinical data suggest that FTIs, alone and in combination with other agents, have antitumor activity. Further study is needed to determine the precise mechanism of FTI antitumor activity as well as how and where FTIs will be best used clinically.

Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Benzodiazepines; Clinical Trials as Topic; Drug Evaluation, Preclinical; Enzyme Inhibitors; Farnesyltranstransferase; Genes, ras; Humans; Imidazoles; Piperidines; Pyridines; Quinolones

Until recently, the therapeutic treatment of breast cancer has been dominated by endocrine-based drugs (oestrogen receptor antagonists, aromatase inhibitors etc.) and conventional cytotoxics (doxorubicin, cyclophosphamide, 5-fluorouracil etc.). However, the advent of new generation signal transduction inhibitor drugs targeted against the molecular abnormalities of breast cancer (e.g., the antibody trastuzumab, directed against the cERBB2 receptor) has the promise of providing a new era of more tumour selective therapy. Inhibitors of the enzyme farnesyl transferase (FTIs) are now undergoing early-stage clinical trials, including in patients with advanced breast cancer. Although originally developed as inhibitors of RAS signal transduction pathways, it is now apparent that these drugs are better described as prenylation inhibitors; the addition of a 15-carbon prenyl or farnesyl moiety by farnesyl transferase being critical to the function of a number of proteins, including RAS. At least three FTIs are currently undergoing clinical evaluation; R115777 (tipifarnib, Zarnestra), SCH66336 (lonafarnib, Sarasar) and BMS-214662. In terms of their potential use in the chemotherapeutic treatment of advanced breast cancer, a Phase II trial of R115777 (using either continuous or intermittent twice-daily oral dosing) has demonstrated promising activity (approximately 10% partial response rate). Overall, however, the single agent activity of FTIs in various Phase II trials has been rather modest (as well as the above mentioned breast cancer trial, some responses have been seen in patients with acute and chronic myeloid leukaemias). The main dose-limiting toxicities that have been reported are myelosuppression and fatigue and neurotoxicity (with R115777). Two Phase III trials of R115777 in colorectal (versus placebo) and pancreatic (with gemcitabine versus placebo) cancer have failed to show a survival benefit. It is likely that the future clinical direction of FTIs will be as combination therapy, especially with the taxanes, where synergy has been seen in a variety of preclinical studies.

Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; Benzodiazepines; Breast Neoplasms; Clinical Trials as Topic; Enzyme Inhibitors; Farnesyltranstransferase; Female; Humans; Imidazoles; Piperidines; Pyridines; Quinolones; ras Proteins

The proto-oncogene Ras requires localization to the intracellular surface of the cellular membrane to exert its mitogenic effects. This subcellular localization is dependent on post-translational modification of the Ras protein, which results in the covalent addition of a lipid hydrophobic moiety to the carboxy-terminal. This post-translational processing is catalyzed by the enzyme farnesyltransferase. This enzyme adds a 15-carbon farnesyl group to the sulfur atom of the cysteine residue in the carboxy-terminal end of the Ras protein. Specific inhibitors of farnesyltransferase have been generated to block the mitogenic function of Ras. These inhibitors can also prevent the post-translational modification and function of many other farnesylated proteins. These include the centromere-associated proteins CENP-E and CENP-F, RhoB and E, the nuclear lamins, and Rap2. Preclinical studies indicate that these agents have a broad spectrum of antitumor activity, blocking proliferation and inducing apoptosis. The lead compounds currently in clinical development are R115,777 and SCH66336. Clinical trials have shown that these compounds can be safely administered, with favorable therapeutic indices, allowing the administration of biologically active doses of drug. Recent phase II clinical trials in patients with metastatic breast carcinoma have shown that R115,777 has reproducible single-agent activity, with activity being predominantly seen in patients with HER2-positive disease. Studies evaluating combined signal transduction blockade with trastuzumab and R115,777 are therefore being pursued, with a phase I study indicating that full-dose R115,777 can be safely administered with full-dose trastuzumab. Efficacy studies of this combination in patients with metastatic breast carcinoma are ongoing. Taxane and farnesyltransferase inhibitor combinations are also being evaluated because preclinical studies suggest that these classes of anticancer agents may be synergistic. Randomized clinical studies investigating the clinical benefits of farnesyltransferase inhibition, with or without a taxane and trastuzumab, in patients with treatment-naive HER2-positive metastatic breast carcinoma are now warranted.

Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Breast Neoplasms; Clinical Trials as Topic; Enzyme Inhibitors; Farnesyltranstransferase; Genes, ras; Humans; Piperidines; Protein Prenylation; Proto-Oncogene Mas; Pyridines; Quinolones; ras Proteins; Signal Transduction

Protein farnesylation catalysed by the enzyme farnesyl protein transferase involves the addition of a 15-carbon farnesyl group to conserved amino acid residues at the carboxyl terminus of certain proteins. Protein substrates of farnesyl transferase include several G-proteins, which are critical intermediates of cell signalling and cytoskeletal organisation such as Ras, Rho, PxF and lamins A and B. Activated Ras proteins trigger a cascade of phosphorylation events through sequential activation of the PI3 kinase/AKT pathway, which is critical for cell survival, and the Raf/Mek/Erk kinase pathway that has been implicated in cell proliferation. Ras mutations which encode for constitutively activated proteins are found in 30% of human cancers. Because farnesylation of Ras is required for its transforming and proliferative activity, the farnesyl protein transferase inhibitors were designed as anticancer agents to abrogate Ras function. However, current evidence suggests that the anticancer activity of the farnesyl transferase inhibitors may not be simply due to Ras inhibition. This review will discuss available clinical data on three of these agents that are currently undergoing clinical trials.

Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Benzodiazepines; Cell Division; Clinical Trials as Topic; Combined Modality Therapy; Enzyme Inhibitors; Farnesyltranstransferase; Genes, ras; Humans; Imidazoles; Neoplasms; Piperidines; Pyridines; Quinolones; Tumor Cells, Cultured

Ras genes encode proteins that activate in an intracellular signaling network controlling differentiation, proliferation and cell survival. Mutated Ras oncogenes encoding proteins that are constitutively active can induce malignancies in a variety of laboratory models. In human malignancies, Ras mutations are common, having been identified in approximately 30% of cancers. Given the importance of Ras and downstream targets Raf and MEK in the development of malignancies and their frequent expression in human cancers, it is not surprising that a variety of agents disrupting signaling through Ras and downstream proteins are under development. These agents can be broadly classified structurally as small molecules and anti-sense oligonucleotides. They can be characterized functionally as those inhibiting Ras protein expression such as the oligodeoxynucleotide ISIS 2503, those inhibiting Ras processing, in particular the farnesyl transferase inhibitors R115777, SCH 66336 and BMS 214662, and those inhibiting downstream effectors Raf, such as ISIS 5132 and MEK, which is inhibited by CI-1040. The purpose of this review is to highlight recent advances in the development of these agents.

Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; Benzamides; Benzodiazepines; Enzyme Inhibitors; Farnesyltranstransferase; Gene Expression Regulation, Neoplastic; Genes, ras; Humans; Imidazoles; MAP Kinase Kinase Kinases; Oligonucleotides, Antisense; Phosphorothioate Oligonucleotides; Piperidines; Proto-Oncogene Proteins c-raf; Pyridines; Quinolones; Signal Transduction

Farnesyltransferase inhibitors (FTIs) belong to a group of agents originally designed to prevent membrane attachment of Ras protein by inhibiting a key step in its post-translational processing. It was thus hypothesized that FTIs would curtail the oncogenic ras-mediated proliferative and antiapoptotic signals that are activated in human tumors. Although the Ras protein is mutated in only < 5% of breast cancers, there are multiple aberrant pathways that lead to activation of wild-type ras signaling. Moreover, FTIs have consistently demonstrated efficacy in tumors regardless of their ras mutational status. Thus, the role of other protein targets in mediating the antitumor effect of FTIs is being elucidated. This article reviews current data on the use of FTIs in breast cancer.

Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Clinical Trials as Topic; Deoxycytidine; Drug Screening Assays, Antitumor; Drug Synergism; Enzyme Inhibitors; Farnesyltranstransferase; Female; Fluorouracil; Humans; Mice; Neoplasm Proteins; Paclitaxel; Piperidines; Protein Prenylation; Protein Processing, Post-Translational; Pyridines; Quinolones; Signal Transduction; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Farnesyltransferase inhibitors represent a new class of agents that target signal transduction pathways responsible for the proliferation and survival of diverse malignant cell types. Although these agents were developed to prevent a processing step necessary for membrane attachment and maturation of Ras proteins, recent studies suggest that farnesyltransferase inhibitors block the farnesylation of additional cellular polypeptides, thereby exerting antitumor effects independent of the presence of activating ras gene mutations. Clinical trials of two farnesyltransferase inhibitors--the tricyclic SCH66336 and the methylquinolone R115777--as single agents have demonstrated disease stabilization or objective responses in 10 to 15% of patients with refractory malignancies. Combinations of farnesyltransferase inhibitors with cytotoxic chemotherapies are yielding complete and partial responses in patients with advanced solid tumors. A phase I trial of R115777 in refractory and relapsed acute leukemias induced responses in 8 (32%) of 25 patients with acute myelogenous leukemia (including two complete remissions) and in two of three with chronic myelogenous leukemia in blast crisis. In patients with solid tumors, accessible normal tissues such as peripheral blood lymphocytes or, perhaps more germane to epithelial malignancies, buccal mucosa have provided surrogate tissues that allow confirmation that farnesyltransferase is inhibited in vivo at clinically achievable drug doses. In conjunction with the R115777 acute leukemia trial, serial measurements provided evidence of farnesyltransferase enzyme inhibition, interference with farnesyltransferase function ( ie, protein processing), and blockade of signal transduction pathways in leukemic bone marrow cells. Preclinical studies of farnesyltransferase inhibitor resistance and clinical trials of farnesyltransferase inhibitors in combination with other agents currently are in progress.

Topics: Alkyl and Aryl Transferases; Clinical Trials as Topic; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Leukemia; Neoplasms; Piperidines; Pyridines; Quinolones; Signal Transduction

The targeting of molecular abnormalities in neoplasms may provide an opportunity to improve the selectivity of cancer therapy. Ras mutations are a common genetic event in human cancers. Other genetic changes in tumors can signal through ras-dependent pathways as well. The targeting of ras through the inhibition of Ras protein farnesylation is one new cancer treatment strategy under clinical evaluation. Several farnesyltransferase inhibitors (FTIs) have been evaluated in phase I trials. The toxicity and maximally tolerated doses of several FTIs have been determined, and clinical trials are underway to evaluate FTIs in combination with conventional cytotoxic chemotherapy agents. Also underway are attempts to develop assays to measure the biological effects of the FTI in patients. Inhibition of farnesylation of a number of surrogate markers are currently being investigated. These efforts may provide insight into the mechanism of action of these compounds and lead to improved patient selection for clinical trials.

Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; Benzodiazepines; Clinical Trials as Topic; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Imidazoles; Piperidines; Pyridines; Quinolones; ras Proteins

The ras family of proto-oncogenes are upstream mediators of several essential cellular signal transduction pathways involved in cell proliferation and survival. Point mutations of ras oncogenes result in constitutive activation of oncogenic Ras. The key step in post-translational processing of Ras protein is farnesylation by farnesyl transferase. Inhibitors of this enzyme were developed initially as a therapeutic strategy for Ras-mutated tumors. Moreover, it is now clear that farnesyl transferase inhibitors (FTIs) have activity independent of Ras, and show some effects on tumors without oncogenic ras mutations. Preclinical data show that FTIs can inhibit proliferation of breast cancer cells in vitro and in vivo, and phase II studies of FTI-R115777 in advanced breast cancer show encouraging results. Therefore, FTIs, used alone or with other agents, may be a novel therapeutic approach for breast cancer.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Proliferation; Enzyme Inhibitors; Farnesyltranstransferase; Female; Genes, ras; Humans; Piperidines; Protein Prenylation; Pyridines; Quinolones; ras Proteins

The shortage of geranylgeranyl-pyrophosphate (GGPP) was associated to an increased IL-1β release in the autoinflammatory syndrome mevalonate kinase deficiency (MKD), a rare inherited disease that has no specific therapy. Farnesyltransferase inhibitors (FTIs) act at the end of mevalonate pathway. Two FTIs, tipifarnib (Tip) and lonafarnib (Lon), were therefore evaluated as possible therapeutical choices for the treatment of MKD. FTIs could lead to a redirection of the limited available number of mevalonate intermediates preferentially to GGPP synthesis, eventually preventing the uncontrolled inflammatory response. The effect of Tip and Lon on intracellular cholesterol level (ICL) and on proinflammatory cytokines secretion was evaluated in a cellular model of MKD, chemically obtained treating RAW 264.7 cells with lovastatin (Lova) and alendronate (Ald). The combination of FTIs with the isoprenoid geraniol (GOH) was also tested both in this model and in monocytes isolated from MKD patients. Tip and Lon proved to revert the ICL lowering and to significantly reduce the lipopolysaccharide-induced cytokines secretion in Ald-Lova -RAW 264.7 cells. This anti-inflammatory effect was amplified combining the use of GOH with FTIs. The effect of GOH and Tip was successfully replicated in MKD patients' monocytes. Tip and Lon showed a dramatic anti-inflammatory effect in monocytes where mevalonate pathway was chemically or genetically impaired.

Topics: Acyclic Monoterpenes; Alendronate; Animals; Anti-Inflammatory Agents; Cell Line; Child; Child, Preschool; Cholesterol; Cytokines; Dose-Response Relationship, Drug; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Inflammation Mediators; Lovastatin; Male; Mevalonate Kinase Deficiency; Mice; Monocytes; Phosphotransferases (Alcohol Group Acceptor); Piperidines; Polyenes; Polyisoprenyl Phosphates; Polyunsaturated Alkamides; Pyridines; Quinolones; Terpenes

The purpose of this work is to study mechanisms underlying anti-tumor effects of farnesyltransferase inhibitors (FTIs) in non-small cell lung cancer (NSCLC). We demonstrate that mRNA and protein levels of Ras homologue enriched in brain (Rheb) are highly expressed both in NSCLC tissues and in NSCLC cell lines. Rheb expression levels correlate with phosphorylation of its downstream target S6 and the sensitivity of NSCLC cells to FTIs (R115777 and SCH66336)-induced growth inhibition and apoptosis. FTIs effectively and preferentially inhibited Rheb downstream signaling in NSCLC cells. Moreover, inhibition of Rheb functions by FTIs or dominant-negative Rheb mutants enhance the effects of cisplatin on NSCLC cells. Rheb-CSVL, a FTIs-resistant mutant, reduces the effects of FTIs on NSCLC cells. Our results suggest that Rheb is a critical target for FTIs therapy in NSCLC.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Cisplatin; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Lung Neoplasms; Mechanistic Target of Rapamycin Complex 1; Monomeric GTP-Binding Proteins; Multiprotein Complexes; Mutation; Neuropeptides; Phosphorylation; Piperidines; Prenylation; Proteins; Pyridines; Quinolones; Ras Homolog Enriched in Brain Protein; Ribosomal Protein S6; RNA Interference; RNA, Messenger; Signal Transduction; TOR Serine-Threonine Kinases; Transcription Factors; Transfection

KRAS mutations are currently the most frequently mutated oncogenes in non-small cell lung cancers (NSCLC). A growing body of evidence suggests that targeting RAS could be an efficient strategy in NSCLC. Several approaches have been developed to target either RAS protein or downstream effectors such as RAF or MEK. First clinical trials evaluating farnesyltransferases inhibitors have led to unsuccessful results. However, targeting RAF and MEK could be a more efficient approach in NSCLC.

Topics: Animals; Antineoplastic Agents; Benzenesulfonates; Carcinoma, Non-Small-Cell Lung; Farnesyltranstransferase; Genes, ras; Humans; Lung Neoplasms; Mice; Mitogen-Activated Protein Kinase Kinases; Mutation; Neoplasm Proteins; Niacinamide; Phenylurea Compounds; Piperidines; Pyridines; Quinolones; raf Kinases; ras Proteins; Sorafenib

Topics: Antineoplastic Agents; Azacitidine; Biomedical Research; Carbazoles; Carboplatin; Cytarabine; Daunorubicin; Decitabine; Enzyme Inhibitors; Etoposide; Flavonoids; Furans; Humans; Leukemia, Myeloid, Acute; Mitoxantrone; Piperidines; Quinolones; Staurosporine; Topotecan; Tretinoin

Several cytoplasmic proteins, such as GTPases of the Ras family, containing a C-terminal CAAX motif are prenylated by farnesyltransferase to facilitate localization to cellular membranes where activation occurs. Farnesyltransferase inhibitors (FTIs) interfere with this farnesylation process, thereby preventing proper membrane localization and rendering the proteins unavailable for activation. Currently, FTIs are being explored as antineoplastic agents for the treatment of several malignancies. However, since farnesylated proteins like Ras are also involved in intracellular signaling in lymphocytes, FTIs might interfere with T-cell activation. Based on this hypothesis we examined the effect of several FTIs on cytokine production in response to anti-CD3 + anti-CD28 monoclonal antibodies or PMA + ionomycin. Murine Th1 and Th2 clones, stimulated in the presence of FTIs, showed a dose-dependent reduction of lineage-specific cytokine secretion (IFN-gamma, IL-2, IL-4, IL-5). However, no inhibition of ERK or JNK MAP kinases was observed, nor was induction of cytokine mRNA affected. Rather, intracellular cytokine protein synthesis was blocked. Inhibition of human T-cell INF-gamma production also was observed, correlating with reduced phosphorylation of p70S6K. These results indicate that FTIs inhibit T-cell activation at the posttranscriptional level and also suggest that they may have potential as novel immunosuppressive agents.

Topics: Antibodies, Monoclonal; Blotting, Western; CD28 Antigens; CD3 Complex; Cells, Cultured; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Farnesyltranstransferase; HSP40 Heat-Shock Proteins; Humans; Interferon-gamma; Interleukin-2; Interleukin-4; Lymphocyte Activation; MAP Kinase Kinase 4; Methionine; Phosphorylation; Piperidines; Protein Prenylation; Pyridines; Quinolones; Ribonuclease, Pancreatic; Ribosomal Protein S6 Kinases, 70-kDa; RNA Processing, Post-Transcriptional; T-Lymphocytes; Th1 Cells; Th2 Cells

Farnesyltransferase inhibitors were initially developed as Ras inhibitors as they inhibit the prenylation necessary for Ras activation. It is clear now that their mechanism of action is more complex and probably involves other proteins unrelated to Ras. At least 3 drugs within this family have been investigated in acute myeloid leukemia, myelodysplastic syndromes, and other leukemias. These are tipifarnib (R115777, Zarnestra), lonafarnib (SCH66336, Sarasar), and BMS-214662. The first 2 are administered orally, whereas BMS-214662 is given intravenously. These drugs are at different stages of development, and design of treatment schedules and methodology of the available studies are very different. Although most of the information is still preliminary, these agents have demonstrated clear evidence of clinical activity in these diseases and very favorable toxicity profiles. Several studies are still ongoing to better define the efficacy of these agents in the treatment of leukemias, as well as to determine the best schedules, the role of combination with other agents, and the role of these agents in different settings, such as the management of minimal residual disease. It is very possible that these agents will soon find their way to the ranks of established agents for the management of myeloid malignancies

Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Benzodiazepines; Clinical Trials as Topic; Farnesyltranstransferase; Humans; Imidazoles; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Piperidines; Pyridines; Quinolones

An international meeting focused on farnesyl transferase inhibitors (FTIs) was held in Naples on 12 April 2002 and represented an excellent occasion to gather most of the clinicians who are involved in clinical trials with this class of new compounds. Oncogene mutations of the gene occur in approximately 30% of all human cancers and may have prognostic significance. Ras protein is normally synthesized as pro-Ras, which undergoes a number of post-translational modifications, among which farnesylation. Processed Ras proteins localize to the inner surface of the plasma membrane, and function as a molecular switch that cycles between an inactive and an active form. When in its active form, either because of the binding of an external ligand or because of its constitutive activation, Ras activates several downstream effectors, such as Raf-1, Rac, Rho and phospahtidylinositol-3 kinase, which mediate important cellular functions, such as proliferation, cytoskeletal organization and others. Interruption of the Ras signaling pathway can be basically achieved in three ways, i.e. inhibition of Ras protein expression through antisense oligonucleotides, prevention of Ras membrane localization and inhibition of Ras downstream effectors. SCH 66336 (lonafarnib; Sarasar), a tricyclic orally active FTI, has been the first of these compounds to undergo clinical development. The toxicity profile observed in all completed phase I/II trials has been fairly similar, since gastrointestinal tract toxicity (nausea, vomiting and diarrhea) and fatigue have generally qualified as dose-limiting toxicity (DLT). One objective response in a patient with pretreated non-small cell lung cancer (NSCLC) was observed. Based on preclinical evidence of synergism between lonafarnib and other anticancer agents, combination studies have been started. In particular, lonafarnib has been combined both with gemcitabine and with paclitaxel in phase I studies. Nausea, vomiting, diarrhea and myelosuppression represented DLTs in these studies, in which an encouraging clinical activity was observed, in particular in pancreatic carcinoma (lonafarnib plus gemcitabine) and in NSCLC (lonafarnib plus paclitaxel). R115777 (Zarnestra) is another novel orally active FT competitive inhibitor in clinical development. Single-agent phase I/II studies have shown that myelotoxicity and neurotoxicity are DLTs, intermittent schedule is probably better tolerated and antitumor activity is observed particularly in breast canc

Topics: Alkyl and Aryl Transferases; Animals; Antineoplastic Agents; Enzyme Inhibitors; Farnesyltranstransferase; Genes, ras; Humans; Piperidines; Pyridines; Quinolones