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PubMed2004

Caveolin-1 gene disruption promotes mammary tumorigenesis and dramatically enhances lung metastasis in vivo. Role of Cav-1 in cell invasiveness and matrix metalloproteinase (MMP-2/9) secretion.

Caveolin-1 (Cav-1) is the principal structural component of caveolae membrane domains in non-muscle cells, including mammary epithelia. There is now clear evidence that caveolin-1 influences the development of human cancers. For example, a dominant-negative mutation (P132L) in the Cav-1 gene has been detected in up to 16% of human breast cancer samples. However, the exact functional role of caveolin-1 remains controversial. Mechanistically, in cultured cell models, Cav-1 is known to function as a negative regulator of the Rasp42/44 MAP kinase cascade and as a transcriptional repressor of cyclin D1 gene expression, possibly explaining its in vitro transformation suppressor activity. Genetic validation of this hypothesis at the in vivo and whole organismal level has been prevented by the lack of a Cav-1 (-/-)-null mouse model. Here, we examined the role of caveolin-1 in mammary tumorigenesis and lung metastasis using a molecular genetic approach. We interbred a well characterized transgenic mouse model of breast cancer, MMTV-PyMT (mouse mammary tumor virus-polyoma middle T antigen), with Cav-1 (-/-)-null mice. Then, we followed the onset and progression of mammary tumors and lung metastases in female mice over a 14-week period. Interestingly, PyMT/Cav-1 (-/-) mice showed an accelerated onset of mammary tumors, with increased multiplicity and tumor burden ( approximately 2-fold). No significant differences were detected between PyMT/Cav-1 (+/+) and PyMT/Cav-1 (+/-) mice, indicating that complete loss of caveolin-1 is required to accelerate both tumorigenesis and metastasis. Molecularly, mammary tumor samples derived from PyMT/Cav-1 (-/-) mice showed ERK-1/2 hyperactivation, cyclin D1 up-regulation, and Rb hyperphosphorylation, consistent with dys-regulated cell proliferation. PyMT/Cav-1 (-/-) mice also developed markedly advanced metastatic lung disease. Conversely, recombinant expression of Cav-1 in a highly metastatic PyMT mammary carcinoma-derived cell line, namely Met-1 cells, suppressed lung metastasis by approximately 4.5-fold. In vitro, these Cav-1-expressing Met-1 cells (Met-1/Cav-1) demonstrated a approximately 4.8-fold reduction in invasion through Matrigel-coated membranes. Interestingly, delivery of a cell permeable peptide encoding the caveolin-1 scaffolding domain (residues 82-101) into Met-1 cells was sufficient to inhibit invasion. Coincident with this decreased invasive index, Met-1/Cav-1 cells exhibited marked reductions in MMP-9 and MMP-2 secretion and associated gelatinolytic activity, as well as diminished ERK-1/2 signaling in response to growth factor stimulation. These results demonstrate, for the first time, that caveolin-1 is a potent suppressor of mammary tumor growth and metastasis using novel in vivo animal model approaches.

Animals↗
PubMed2005

Transgenic animal models of tauopathies.

Tauopathies are a group of neurodegenerative disorders that include Alzheimer's disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and other related diseases with prominent tau pathology. Research advances in the last several decades have characterized and defined tau neuropathologies of both neuron and glia in these diverse disorders and this has stimulated development of animal models of tauopathies. Indeed, animal models ranging from invertebrate species such as C. elegan to Drosophila melanogaster and mammalian transgenic mouse models of tauopathies have been generated and reported. This review summarizes the salient features of many of the known models of tauopathies.

Animals↗
PubMed2002

Loss of Stat5a delays mammary cancer progression in a mouse model.

A genetic study was conducted to determine if activated Stat5a contributes to mammary carcinogenesis and to evaluate the mechanism. Similar to human breast cancers, a proportion of mammary adenocarcinomas in the WAP-TAg transgenic mouse model demonstrate constitutive Stat5a/b and Stat3 activation. Stat5a activation is linked to mammary epithelial cell survival and differentiation, and proliferation in hematopoetic cell lineages. Breeding WAP-TAg mice to mice carrying germ-line deletions of the Stat5a gene generated mice with reduced levels of Stat5a. Hemizygous loss of the Stat5a allele significantly reduced levels of Stat5a expression without altering mammary gland development or transgene expression levels. In comparison to mice carrying two wild-type Stat5a alleles, hemizygous loss of the Stat5a allele reduced the number of mice with palpable tumors at 7 months of age (67% from 100%, P<0.05), resulted in smaller tumors at 7 months of age (3.8 cm3 from 7.6 cm3, P=0.003), delayed first tumor appearance (208 days from 188 days, P=0.01), and increased the apoptotic index in the adenocarcinomas (4.3+/-0.3 from 1.2+/-0.2, P=0.016). Neither cell proliferation nor differentiation in the cancers was altered. Decreasing Stat5a activation levels could be a therapeutic approach for reducing survival of breast cancer cells.

Adenocarcinoma↗
PubMed1993

Specific atrial overexpression of G protein coupled human beta 1 adrenoceptors in transgenic mice.

OBJECTIVE: The aim was to develop a transgenic mouse model of atrial beta 1 adrenoceptor overexpression in order to create atrial alteration of the receptor transduction system. METHODS: Transgenic founders were generated after microinjection of the transgene construct into the pronucleus of fertilised mouse eggs. Heterozygous progeny were screened for RNA expression of the human beta 1 adrenoceptor gene under the control of a 0.56 kb proximal promoter of the human atrial natriuretic factor. One line, out of the three obtained, was selected and further characterised for overexpression of the human beta 1 adrenoceptor. Polymerase chain reaction was employed to detect beta 1 adrenoceptor mRNA, and 125I-cyanopindolol (ICYP) binding assays were used to quantify receptors in heart membranes. A quantitative autoradiographic ICYP binding technique was also used to visualise atrial and ventricular beta adrenoceptors in heart sections. RESULTS: The human beta 1 adrenoceptor was overexpressed specifically in the atria of transgenic mice. The level of the beta 1 adrenoceptor was 5-10-fold higher in transgenic mice compared to basal murine beta 1 adrenoceptors in non-transgenic control mice. Left and right atrial receptor overexpression was confirmed by in vitro autoradiography. The human receptors were able to couple to the murine stimulatory G proteins (Gs), as shown by high affinity binding site dosage using the beta adrenoceptor agonist isoprenaline. Isoprenaline displacement studies allowed the determination of two different affinity sites, one of high affinity (KH = 5.8 nM), and one of low affinity (KL = 520 nM). When expressed in terms of protein density (fmol.mg-1), atrial transgenic beta 1 adrenoceptors displayed a threefold increase in high affinity sites (KH) as compared to control mice. Preliminary electrocardiographic data showed supraventricular premature beats in 6/14 transgenic mice v 2/16 control mice. CONCLUSIONS: These transgenic mice may provide a useful pharmacological tool to investigate the pathophysiological consequences of the overactivation of atrial beta 1 adrenoceptor-adenylyl cyclase signalling system.

Animals↗
PubMed2006

A decade of modeling Alzheimer's disease in transgenic mice.

It has been over a decade since the first Alzheimer's disease (AD) transgenic mouse models were reported. These models have enabled dramatic advances in our understanding of the pathogenic mechanism in AD and of potential therapeutic approaches to tackling the inexorable clinical progression of the disease. In this article, we discuss the current status of AD mouse models and focus on recent work that has examined the development of the neuropathological lesions observed in AD (plaques and tangles). The relationship between these lesions, neurodegeneration and development of the clinical syndrome will be explored.

Alzheimer Disease↗
PubMed1989

[Transgenic mice and their use in cancer study].

The ability to introduce the cloned gene into the mouse germ line has made possible to analyze the cis-acting DNA sequence which is involved in the tissue-specific and developmental regulation of the gene. In addition, this system can also be applied to analyze the patho-physiological roles of the introduced gene product within the mouse whole body. Therefore, this system is one of the best approaches to analyze the mechanism of oncogenesis. The chromosomal translocation is one of the mechanisms leading to the activation of oncogene. In the case of lymphoid cell tumors, the reciprocal translocation between chromosome No. 8 and No. 14 is frequently observed. With this translocation, c-myc gene can be activated by the enhancer of immunoglobulin heavy chain (E mu). We and others have demonstrated that the E mu-myc gene could induce lymphomas in transgenic mice. Following these observation we have currently many examples that activated oncogene can induce variety tumors, giving basic knowledge about the relationship between activated oncogene and cell-type specificity of tumor. On the other hand, molecular mechanism of oncogenesis which is caused by viruses such as hepatitis B virus (HBV) or human T cell leukemia virus (HTLV) is totally unknown. One main reason is the absence of animal model for these diseases. To overcome this problem, we have attempted and succeeded to produce a transgenic mouse model which consistently produces HBV. Using these mice, it will be possible to elucidate the molecular mechanism of development of hepatitis and hepatocellular carcinoma.

Animals↗
PubMed1998

Antisense c-myc and immunostimulatory oligonucleotide inhibition of tumorigenesis in a murine B-cell lymphoma transplant model.

BACKGROUND: Because the development of drug-resistant cells can lead to relapses in patients with lymphoma treated with chemotherapy, new approaches are needed for effective disease management, such as those targeting the c-MYC proto-oncogene with antisense oligonucleotides. Our goal was to investigate whether antisense c-myc oligonucleotides could prevent tumorigenesis in a B-cell lymphoma model. METHODS: Immunocompetent mice received subcutaneous injections of tumor cells from a transgenic mouse model of Burkitt's lymphoma. For 7 consecutive days, beginning 1 day after tumor cell transplantation, the mice were given either a DNA phosphorothioate oligonucleotide complementary to c-myc codons 1-5 (myc6) or other c-myc-related oligonucleotides at a dose of 0.76 mg per day subcutaneously. Myc protein expression, normalized to beta-actin expression, was measured by western blotting of tumor and splenic proteins. To determine whether tumor inhibition by myc6 could be a result of B-cell activation, we compared the activity of myc6 with that of an immunostimulatory oligonucleotide, mcg. RESULTS: In comparison with control treatments (saline vehicle, scrambled-sequence oligonucleotide, or double-mismatch oligonucleotide), treatment with myc6 delayed tumor onset by 3 days, decreased total tumor mass at sacrifice (i.e., 17 days after tumor cell transplantation) by 40% +/- 16% (mean +/- standard error), and decreased the splenic Myc-to-actin ratio. Inhibition of tumors by myc6 and mcg (both of which share a dACGTT motif) was comparable. Administration of an oligonucleotide sequence complementary to c-myc codons 384-388 (myc55) delayed tumor onset by 5-6 days, decreased total tumor mass at sacrifice by 65% +/- 6%, and reduced the splenic Myc-to-actin ratio to below that produced by myc6. A 14-day treatment regimen of myc55 alternating with mcg completely inhibited tumor formation during the therapeutic schedule. CONCLUSIONS: A combined oligonucleotide regimen, based on antisense c-MYC and immunostimulatory oligonucleotides, should be investigated to increase the number and duration of complete remissions obtained after standard chemotherapy for B-cell lymphoma.

Adjuvants, Immunologic↗
PubMed1999

HLA class II transgenic mice: models of the human CD4+ T-cell immune response.

This review examines the field of current HLA class II transgenic mouse models and the individual approaches applied in production of these mice. The majority of these mice have been created with the objective of obtaining a disease model with clinical features mimicking human autoimmune disease. The development process of a different type of HLA class II transgenic mice, which are designed to function as a substitute for a normal human immune system in studies of human autoantigens, is described. Several HLA-DR4 transgenic lines with normally expressed HLA-DR4 molecules have been produced. To obtain adequate positive selection of the HLA-DR4-restricted CD4+ T-cell repertoire in these mice it is essential both to introduce a human CD4 transgene, and to delete the murine major histocompatibility complex (MHC) class II molecules. These HLA-DR4 transgenic mice have been used to determine the immunogenic CD4+ T-cell epitopes of several human autoantigenic proteins.

Animals↗
PubMed1994

Regulatory imbalances in cell proliferation and cell death during oncogenesis in transgenic mice.

Whether a cell decides to proliferate, undergo growth arrest, or even commit suicide is determined by a multitude of highly potent positive and negative regulatory factors. Mutational perturbation of these factors and the normal pathways through which they regulate either cell proliferation or cell death can induce a pathologic enhancement in cell number, or hyperplasia, and eventually the development of malignant tumors. Serving as valuable animal models for cancer in humans, transgenic mice have been used to demonstrate the dramatic consequences of subverting the normal molecular mechanisms regulating cell proliferation and/or cell death. This review will use three transgenic mouse models to illustrate the consequences of inducing such regulatory imbalances, as well as the utility and versatility of the transgenic approach in cancer research. Three different regulatory factors are considered; transforming growth factor-alpha is discussed as an example of a positive growth regulator, p53 as a negative growth regulator, and Bcl-2 as an inhibitor of programmed cell death.

Animals↗
PubMed2003

Allelic loss of p53 gene is associated with genesis and maintenance, but not invasion, of mouse carcinoma in situ of the bladder.

Carcinoma in situ (CIS) of the bladder has recently been proposed to be a heterogeneous group of diseases with varied histogenesis and biological behavior. In this study, we describe the sequential steps of CIS development and progression in a transgenic mouse model expressing low levels of the SV40 large T antigen. We found that CIS in transgenic mice arose from urothelial dysplasia, that CIS could persist for an extended period of time without invasion, and that the majority of CIS eventually evolved into high-grade, superficial, papillary tumors before a small fraction of them advanced to invasion/metastasis. A genome-wide search of chromosomal imbalances by comparative genomic hybridization revealed that 9 of 11 (82%) of CIS had losses on chromosome 11. Southern blotting demonstrated the allelic loss of the p53 gene, which resides on mouse chromosome 11, in four comparative genomic hybridization-tested tumors and 10 of 11 (91%) additional CIS examined. Consistent with the reduced p53 gene dosage because of the allelic loss and the functional inactivation of p53 protein of the remaining allele by SV40T antigen, there was a dramatic decrease in CIS of Mdm-2, a major p53 target. In contrast, the level of p21, another p53 target, was largely unaltered, suggesting that p21 expression can be regulated by p53-independent mechanisms. These results delineate the early stages of bladder tumorigenesis and suggest that the loss of a p53-bearing chromosome is an early event in bladder tumorigenesis and is crucial for the genesis and the maintenance, but not the progression, of bladder CIS. On the basis of our current and previous transgenic studies, we have proposed an integrated pathway progression model of bladder cancer.

Alleles↗
PubMed1995

Long-term antidepressant treatment reduces behavioural deficits in transgenic mice with impaired glucocorticoid receptor function.

Impaired cognitive function and enhanced activity of the hypothalamic-pituitary-adrenocortical system are among the cardinal symptoms of major depression in humans that resolve after successful antidepressant treatment. We used a transgenic mouse model expressing antisense RNA complementary to that of glucocorticoid receptor (GR) mRNA to test the hypothesis that reduced GR function can cause these clinical disturbances. The transgenic mice show profound behavioural changes in a number of animal tests that are indicative of cognitive impairment. These mice also have elevated plasma corticotropin concentrations in response to stress. After long-term treatment with moclobemide, a reversible inhibitor of monoamine oxidase type A that acts clinically as an antidepressant, both the behavioural deficits and the hormonal alterations disappeared. These observations suggest that a transgenic mouse with GR dysfunction may be a useful model for investigation of drug effects on the cognitive and neuroendocrine aspects of depression.

Animals↗
PubMed2002

In vivo genotoxicity evaluation of dimethylarsinic acid in MutaMouse.

Dimethylarsinic acid (DMA) induces DNA damage in the lung by formation of various peroxyl radical species. The present study was conducted to evaluate whether arsenite or its metabolite, DMA, could initiate carcinogenesis via mutagenic DNA lesions in vivo that can be attributed to oxidative damage. A transgenic mouse model, MutaMouse, was used in this study and mutations in the lacZ transgene and in the endogenous cII gene were assessed. When DMA was intraperitoneally injected into MutaMice at a dose of 10.6 mg/kg per day for 5 consecutive days, it caused only a weak increase in the mutant frequency (MF) of the lacZ gene in the lung, which was at most 1.3-fold higher than in the untreated control animals. DMA did not appreciably raise the MF in the bladder or bone marrow. Further analysis of the cII gene in the lung, the organ in which DMA induced the DNA damage, revealed only a marginal increase in the MF. Following DMA administration, no change in the cII mutation spectra was observed, except for a slight increase in the G:C to T:A transversion. Administration of arsenic trioxide (arsenite) at a dose of 7.6 mg/kg per day did not result in any increase in the MF of the lacZ gene in the lung, kidney, bone marrow, or bladder. Micronucleus formation was also evaluated in peripheral blood reticulocytes (RETs). The assay for micronuclei gave marginally positive results with arsenite, but not with DMA. These results suggest that the mutagenicity of DMA and arsenite might be too low to be detected in the MutaMouse.

Animals↗
PubMed1998

A causal role for E-cadherin in the transition from adenoma to carcinoma.

Development of malignant tumours is in part characterized by the ability of a tumour cell to overcome cell-cell adhesion and to invade surrounding tissue. E-cadherin is the main adhesion molecule of epithelia, and it has been implicated in carcinogenesis because it is frequently lost in human epithelial cancers. Re-establishing the functional cadherin complex in tumour cell lines results in a reversion from an invasive to a benign epithelial phenotype. However, it remained unresolved whether the loss of E-cadherin-mediated cell adhesion was a cause or a consequence of tumour progression in vivo. Here we report that the loss of E-cadherin expression coincides with the transition from well differentiated adenoma to invasive carcinoma in a transgenic mouse model of pancreatic beta-cell carcinogenesis (Rip1Tag2). Intercrossing Rip1Tag2 mice with transgenic mice that maintain E-cadherin expression in beta-tumour cells results in arrest of tumour development at the adenoma stage, whereas expression of a dominant-negative form of E-cadherin induces early invasion and metastasis. The results demonstrate that loss of E-cadherin-mediated cell adhesion is one rate-limiting step in the progression from adenoma to carcinoma.

Adenoma, Islet Cell↗
PubMed2003

Sarcoplasmic reticulum calcium defect in Ras-induced hypertrophic cardiomyopathy heart.

The small G protein Ras-mediated signaling pathway has been implicated in the development of hypertrophy and diastolic dysfunction in the heart. Earlier cellular studies have suggested that the Ras pathway is responsible for reduced L-type calcium channel current and sarcoplasmic reticulum (SR) calcium uptake associated with sarcomere disorganization in neonatal cardiomyocytes. In the present study, we investigated the in vivo effects of Ras activation on cellular calcium handling and sarcomere organization in adult ventricular myocytes using a newly established transgenic mouse model with targeted expression of the H-Ras-v12 mutant. The transgenic hearts expressing activated Ras developed significant hypertrophy and postnatal lethal heart failure. In adult ventricular myocytes isolated from the transgenic hearts, the calcium transient was significantly depressed but membrane L-type calcium current was unchanged compared with control littermates. The expressions of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)2a and phospholamban (PLB) were significantly reduced at mRNA levels. The amount of SERCA2a protein was also modestly reduced. However, the expression of PLB protein and gross sarcomere organization remained unchanged in the hypertrophic Ras hearts, whereas Ser(16) phosphorylation of PLB was dramatically inhibited in the Ras transgenic hearts compared with controls. Hypophosphorylation of PLB was also associated with a significant induction of protein phosphatase 1 expression. Therefore, our results from this in vivo model system suggest that Ras-induced contractile defects do not involve decreased L-type calcium channel activities or disruption of sarcomere structure. Rather, suppressed SR calcium uptake due to reduced SERCA2a expression and hypophosphorylation of PLB due to changes in protein phosphatase expression may play important roles in the diastolic dysfunction of Ras-mediated hypertrophic cardiomyopathy.

Animals↗
PubMed2006

Immunoediting of cancers may lead to epithelial to mesenchymal transition.

Tumors evade both natural and pharmacologically induced (e.g., vaccines) immunity by a variety of mechanisms, including induction of tolerance and immunoediting. Immunoediting results in reshaping the immunogenicity of the tumor, which can be accompanied by loss of Ag expression and MHC molecules. In this study, we evaluated immunoediting in the neu-transgenic mouse model of breast cancer. A tumor cell line that retained expression of rat neu was generated from a spontaneous tumor of the neu-transgenic mouse and, when injected into the non-transgenic parental FVB/N mouse, resulted in the development of a strong immune response, initial rejection, and ultimately the emergence of neu Ag-loss variants. Morphologic and microarray data revealed that the immunoedited tumor cells underwent epithelial to mesenchymal transition accompanied by an up-regulation of invasion factors and increased invasiveness characteristic of mesenchymal tumor cells. These results suggest that immunoediting of tumor results in cellular reprogramming may be accompanied by alterations in tumor characteristics including increased invasive potential. Understanding the mechanisms by which tumors are immunoedited will likely lead to a better understanding of how tumors evade immune detection.

Animals↗
PubMed1994

Fetal hemoglobin induction by acetate, a product of butyrate catabolism.

Butyrate induces fetal hemoglobin (HbF) synthesis in cultures of erythroid progenitors, in primates, and in man. The mechanism by which this compound stimulates gamma-globin synthesis is unknown. In the course of butyrate catabolism, beta oxidation by mitochondrial enzymes results in the formation of two acetate molecules from each molecule of butyrate. Studies were performed to determine whether acetate itself induces HbF synthesis. In erythroid burst-forming unit (BFU-E) cultures from normal persons, and individuals with sickle cell disease and umbilical-cord blood, dose-dependent increases in gamma-globin protein and gamma mRNA were consistently observed in response to increasing acetate concentrations. In BFU-E cultures from normal adults and patients with sickle cell disease, the ratio of gamma/gamma + beta mRNA increased twofold to fivefold in response to acetate, whereas the percentage of BFU-E progeny staining with an anti-gamma monoclonal antibody (MoAb) increased approximately twofold. Acetate-induced increases in gamma-gene expression were also noted in the progeny of umbilical cord blood BFU-E, although the magnitude of change in response to acetate was less because of a higher baseline of gamma-chain production. The effect of acetate on HbF induction in vivo was evaluated using transgenic mouse and primate models. A transgenic mouse bearing a 2.5-kb mu locus control region (mu LCR) cassette linked to a 3.3-kb A gamma gene displayed a near twofold increase in gamma mRNA during a 10-day infusion of sodium acetate at a dose of 1.5 g/kg/d. Sodium acetate administration in baboons, in doses ranging from 1.5 to 6 g/kg/d by continuous intravenous infusion, also resulted in the stimulation of gamma-globin synthesis, with the percentage of HbF-containing reticulocytes (F reticulocytes) approaching 30%. Surprisingly, a dose-response effect of acetate on HbF induction was not observed in the baboons, and HbF induction was not sustained with prolonged acetate administration. These results suggest that both two-carbon fatty acids (acetate) and four-carbon fatty acids (butyrate) stimulate synthesis of HbF in vivo.

Acetates↗
PubMed1996

Early occurrence of metastatic differentiated thyroid carcinomas in transgenic mice expressing the A2a adenosine receptor gene and the human papillomavirus type 16 E7 oncogene.

We report here the characterization of a transgenic mouse model (Tg-A2aR/Tg-E7) resulting from the coexpression of two oncogenic transgenes in the thyroid. The two transgenes (Tg-A2aR and Tg-E7) were placed under control of the thyroid specific thyroglobulin gene promoter, and directed the expression of either the A2a adenosine receptor that constitutively activates the cAMP pathway, or the E7 protein of the human papillomavirus type 16, that binds and inactivates the retinoblastoma susceptibility gene product (Rb1). Transgenic mice expressing both transgenes were generated by interbreeding the Tg-A2aR and Tg-E7 transgenic lines, generated and characterized previously (Ledent et al., 1992, 1995). These mice develop a larger goiter than that of the two parental lines, and a severe hyperthyroidism comparable to that observed in the Tg-A2aR parental line. The main feature of the Tg-A2aR/Tg-E7 mice is the rapid occurrence of malignant lesions, and the dissemination of malignant thyroid tissue through the blood stream, generating multiple differentiated and functional metastases in the lung. These metastases appeared as early as 2 months after birth and their frequency increased to 75% over 3 months. They were associated with the presence of large vascular lakes in the thyroid. Electron microscopy of the malignant cells revealed nuclear features similar to those of human thyroid papillary carcinoma. These mice, in which two oncogenes are co-expressed in the thyroid, represent the first genetic animal model developing metastatic differentiated carcinomas of the thyroid with a high frequency.

Animals↗
PubMed1997

[Inhibitors of isoprenylation of ras p21].

Posttranslational modification and membrane localization are critical for the function of products of ras oncogenes which are frequently founded to be mutated in human tumors. Farnesylation by farnesyltransferase (FTase) is the first and obligatory step in the processing of ras p21, and FTase has attracted attention as a new target of anticancer agents. Many FTase inhibitors have been identified or synthesized in random screening, and studies on FPP analogs, CAAX analogs, and bisubstrate analogs. These inhibitors induced flat reversion and inhibited the anchorage-independent growth of ras transformant and ras-mutated human tumor cells through the inhibition of posttranslational modification of ras p21. B1086, L-739,749, L-744,832 and FTI-276, which are CAAX analogs, were reported to show inhibition of tumor growth in ras-mutated human tumor xenograft models and to induce regression of mammary and salivary carcinoma in ras transgenic mouse model. FTase inhibitors have the potential to be developed as therapy for ras-mutated human tumors. On the other hand, it has been reported that K-ras 4B p21 could be modified by geranylgeranyltransferase (GGTase). Therefore, GGTase inhibitors have also been evaluated in addition to FTase inhibitors.

Alkyl and Aryl Transferases↗