A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synthesized. Compared with previously described linear 3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as 49 combined improved pharmacokinetic properties with a reduced potential for side effects. In dogs, oral bioavailability was good to excellent, and increases in plasma half-life were due to attenuated clearance. It was observed that in vivo clearance correlated with the flexibility of the molecules and this concept proved useful in the design of FTIs that exhibited low clearance, such as FTI 78. X-ray crystal structures of compounds 49 and 66 complexed with farnesyltransferase (FTase)-farnesyl diphosphate (FPP) were determined, and they provide details of the key interactions in such ternary complexes. Optimization of this 3-aminopyrrolidinone series of compounds led to significant increases in potency, providing 83 and 85, the most potent inhibitors of FTase in cells described to date.

BACKGROUND

The recurrence rates of atrial fibrillation (Af) after ablation are still high, and repeat procedures are required in these patients. The main reason for Af recurrence is the recovery of the conduction between the pulmonary veins and left atrium. The importance of catheter stability during the pulmonary vein isolation (PVI) is not well studied.

OBJECTIVE

The purpose of this study was to evaluate the contact force (CF), stable ablation time, and power during conduction blocking lesion formation for PVI.

METHODS

Thirty-two consecutive drug-refractory Af patients who underwent an initial PVI using CARTO 3 and Visitag were included. The CF, ablation time, force time integral (FTI), and ablation power were recorded by Visitag. Residual conduction gap points requiring touch-up ablation after an encircling linear ablation (R point), spontaneous reconnection points (S point), and dormant conduction points (D point) were considered as non-conduction blocking lesion points. Each ablation parameter for the non-conduction blocking lesion points was compared with the other lesion points.

RESULTS

Twenty-one points in 16 patients were considered non-conduction blocking lesions. Ten were R, eight were S, and three were D points. The CF, ablation time, FTI, and power at the non-conduction blocking lesion points and other points were 12.0 g (7.0-21.5) and 12.0 g (9.0-16.0) (P = 0.9), 7.7 s (5.6-10.1) and 12.5 s (9.4-16.8) (P < 0.05), 103.0 g*s (62.0-174.5) and 149.0 g*s (104.0-213.0) (P < 0.05), and 30.0 W (22.5-30.0) and 30.0 W (30.0-30.0) (P = 0.06), respectively.

CONCLUSIONS

Shorter ablation time recorded in Visitag lead to non-conduction blocking lesion.

OBJECTIVE

The effects of human immunodeficiency virus (HIV) infection on thyroid function have been reported in only a few studies with discrepant results. The aim of this study was to assess the relation between nutritional status and thyroid function in HIV infected patients.

METHODS

Prospective, cross-sectional study.

METHODS

A 500-bed teaching and referral hospital serving a population of 450,000.

METHODS

Seventy-five consecutive HIV infected patients between 21 and 40 years of age (mean 31.8 +/- 0.9 years).

METHODS

Nutritional status was evaluated using the body mass index (BMI), triceps skinfold thickness (TSF), mid-arm muscle circumference (MAMC), and serum albumin concentration (SA). Hormone assays for serum T4, free thyroxine index (FTI), T3, reverse triiodothyronine (rT3), thyroxine-binding globulin (TBG), TSH and simultaneous CD4 lymphocyte counts were determined in all patients.

RESULTS

Clinical stage was significantly related to nutritional status (P = 0.0001 for BMI, P = 0.0002 MAMC). The more poorly nourished groups had low mean serum T3 and rT3 levels, particularly for muscular (P = 0.0001 for T3 and P = 0.0076 for rT3) and visceral (P = 0.00001 for T3 and P = 0.0021 for rT3) protein compartments. Multivariate analysis showed that two factors, SA and MAMC, correlated significantly and independently with serum T3 and rT3.

CONCLUSIONS

A close relation exists between serum thyroid hormone levels and nutritional status in HIV infected patients. These patients are probably euthyroid and the abnormal findings in the thyroid function tests are thus a reflection of the severity of illness.

Manumycin-A (Man-A) is a farnesyltransferase inhibitor (FTI), which was originally identified as an effective tumoricide against several cancers, especially ones harboring constitutively active Ras. However, it is becoming apparent that Man-A can stimulate tumor death independently of FTases. Antioxidant treatment blocked Man-A-stimulated DNA damage and reversed Man-A-inhibited tumor growth. However, the precise molecular details of how these reactive oxygen species (ROS) influence cell signaling modules are poorly understood. We examined how ROS may modulate death and survival pathways in a panel of tumor cells. Man-A treatment resulted in a massive induction of superoxide anion (.O(2) (-)) only in Man-A-sensitive tumors. Within 1 hr, Man-A caused the ROS-dependent activation of caspases 9 and 3. In this time-frame, the Ras-Raf target, MEK, and the survival protein Akt were dephosphorylated in ROS-dependent fashions and then cleaved in ROS and caspase-dependent manners. Pretreatment with ROS scavengers blocked the adverse effects of Man-A, including the processing of caspases and the cleavage of MEK and Akt. These events were noted before any losses in Ras activity or changes in its maturation could be detected. Finally, transfection with cDNAs encoding the antioxidant enzymes catalase, superoxide dismutase and thioredoxin reductase inhibited superoxide induction and apoptosis. Together, our data suggest that the elimination of tumors by Man-A can be independent of the inhibiting of Ras. However, one universal feature observed is the generation of death-triggering intracellular oxidants that appear to directly participate in the select targeting of growth and survival proteins that then either augment or ensure tumor cell death.

Protein farnesyltransferase (FTase) is a zinc-dependent enzyme that catalyzes the attachment of a farnesyl lipid group to the sulfur atom of a cysteine residue of numerous proteins involved in cell signaling including the oncogenic H-Ras protein. Pharmacophore models were developed by using Catalyst HypoGen program with a training set of 22 farnesyltransferase inhibitors (FTIs), which were carefully selected with great diversity in both molecular structure and bioactivity for discovering new potent FTIs. The best pharmacophore hypothesis (Hypo 1), consisting of four features, namely, one hydrogen-bond acceptor (HBA), one hydrophobic point (HY), and two ring aromatics (RA), has a correlation coefficient of 0.961, a root mean square deviation (RMSD) of 0.885, and a cost difference of 62.436, suggesting that a highly predictive pharmacophore model was successfully obtained. For the test series, a classification scheme was used to distinguish highly active from moderately active and inactive compounds on the basis of activity ranges. Hypo 1 was validated with 181 test set compounds, which has a correlation coefficient of 0.713 between estimated activity and experimentally measured activity. The model was further validated by screening a database spiked with 25 known inhibitors. The model picked up all 25 known inhibitors giving an enrichment factor of 10.892. The results demonstrate that the hypothesis derived in this study can be considered to be a useful and reliable tool in identifying structurally diverse compounds with desired biological activity.

Activation of estrogen receptors (ERs) by estrogens triggers both ER nuclear transcriptional activity and Src/Ras/Erks pathway-dependent mitogenic activity. The present study implicates prenylated proteins in both estrogenic actions. The farnesyltransferase and geranylgeranyltransferase I inhibitors (FTI-277 and GGTI-298, respectively) antagonize estradiol-stimulated cell cycle progression, progesterone receptor, cyclin D1, and c-Myc expression. In contrast, the inhibitors markedly stimulate transcription from two genes containing estrogen response elements, both in the absence and presence of estradiol. The pure antiestrogen ICI 182,780 inhibits by more than 85% these effects on transcription. We demonstrate that both FTI-277 and GGTI-298 increase the association of steroid receptor coactivator-1 with ER alpha and FTI-277 decreases the association of ER alpha with the histone deacetylase 1, a known transcriptional repressor. In addition, FTI-277 has no marked effect on the association of the two corepressors, nuclear receptor corepressor and silencing mediator of retinoid and thyroid receptor with ER alpha, whereas GGTI-298, similar to tamoxifen, clearly increased these associations. Together, these results demonstrate that prenylated proteins play a role in estradiol stimulation of proliferation and progesterone receptor expression. However, they antagonize the ability of ER alpha to stimulate estrogen response element-dependent transcriptional activity, acting presumably through coregulator complex formation.

BACKGROUND

Despite the acceptance of gemcitabine as the standard first-line agent for the treatment of advanced pancreatic cancer as well as the improved response rates seen with gemcitabine combinations, novel therapies are needed for this disease, which has one of the lowest survival rates. The growing understanding of the molecular basis of pancreatic cancer and the recent introduction of targeted therapeutic agents have initiated novel studies that have the potential to improve on existing treatments.

METHODS

We review the rationale and the clinical studies of therapeutic agents that target some of the molecular abnormalities commonly found in pancreatic cancer.

RESULTS

Matrix metalloproteinase inhibitors (MMPIs), farnesyltransferase inhibitors (FTIs), and tyrosine-kinase inhibitors and monoclonal antibodies against growth factors or their receptors are novel agents that have undergone phase II or III trials. Phase III studies of MMPIs, alone or in combination with gemcitabine, and phase III studies of FTIs have produced disappointing results. Other agents in earlier phases of clinical development remain promising.

CONCLUSIONS

Despite the negative studies of MMPIs and FTIs, the results of phase II trials of other drugs are encouraging. Targeted agents may improve the prognosis of pancreatic cancer.

OBJECTIVE

To investigate the production of xylitol by the yeast Candida guilliermondii FTI 20037, in a bioreactor, from rice straw hemicellulosic hydrolysate with a high xylose concentration.

RESULTS

Batch fermentation was carried out with rice straw hemicellulosic hydrolysate containing about 85 g xylose l(-1), in a stirred-tank bioreactor at 30 degrees C, under aeration of 1.3 vvm (volume of air per volume of medium per min) and different stirring rates (200, 300 and 500 rev min(-1)). The bioconversion of xylose into xylitol by the yeast depended on the stirring rate, the maximum xylitol yield (YP/S = 0.84 g g(-1)) being achieved at 300 rev min-1, with no need to pretreat the hydrolysate for purification.

CONCLUSIONS

To determine the most adequate oxygen transfer rate is fundamental to improving the xylose-to-xylitol bioconversion by C. guilliermondii.

CONCLUSIONS

For the microbial production of xylitol to be economically viable, the initial concentration of xylose in the lignocellulosic hydrolysate should be as high as possible, as with high substrate concentrations it is possible to increase the final product concentration. Nevertheless, there are few reports on the use of high xylose concentrations. Considering a process in bioreactor, from rice straw hemicellulosic hydrolysate, this is an innovator work.

3D-QSAR analysis of a set of 37 analogues of SCH 66336 (Sarasar) was performed by most widely used computational tool, molecular field analysis (MFA) to investigate the substitutional requirements for the favorable receptor-drug interaction and to derive a predictive model that may be used for the designing of a novel farnesyltransferase inhibitors (FTIs). Regression analysis was carried out using genetic partial least squares (G/PLS) method. A highly predictive and statistically significant model was generated. The predictive ability of the model developed was assessed using a test set of six compounds (r(2)(pred) as high as 0.791). The analyzed MFA model has demonstrated a good fit, having r(2) value of 0.967 and cross-validated coefficient r(2)(cv) value as 0.921.

Farnesyl transferase inhibitors (FTIs) have so far proved to have limited value as single agents in clinical trials. This PharmSight will focus on the use of a novel group of FTIs that are most effective in vitro when used in combination with the "statin" class of anti-hypercholesterolemic agents, which also block protein prenylation. We recently showed that these novel FTIs in combination with lovastatin reduce Ras prenylation and induce an apoptotic response in malignant peripheral nerve sheath cells. The combination of statins with these new FTIs may produce profound synergistic cytostatic and cytotoxic effects against a variety of tumors and other proliferative disorders. Since statins are well tolerated in the clinic, we suggest that this combination approach should be tested in in vivo models.

We studied the effects of fibroblast growth factor (FGF-10) on alveolar epithelial cell (AEC) Na,K-ATPase regulation. Within 30 min FGF-10 increased Na,K-ATPase activity and alpha1 protein abundance by 2.5-fold at the AEC plasma membrane. Pretreatment of AEC with the mitogen-activated protein kinase (MAPK) inhibitor U0126, a Grb2-SOS inhibitor (SH3-b-p peptide), or a Ras inhibitor (farnesyl transferase inhibitor (FTI 277)), as well as N17-AEC that express a Ras dominant negative protein each prevented FGF-10-mediated Na,K-ATPase recruitment to the AEC plasma membrane. Accordingly, we provide first evidence that FGF-10 upregulates (short-term) the Na,K-ATPase activity in AEC via the Grb2-SOS/Ras/MAPK pathway.

Acute leukemia carries a poor prognosis, especially in older patients, emphasizing the need for novel therapies. Reasons for treatment failure include high rates of relapse and treatment-related toxicities. Farnesyltransferase inhibitors (FTIs), a new class of agents that can interfere with intracellular signaling, are good therapeutic candidates for study in these diseases, given the relatively high levels of the target enzyme, farnesyltransferase, expressed in bone marrow and by peripheral circulating lymphocytes. ZARNESTRA (formerly R115777, Ortho Biotech Oncology, Raritan, NJ) is an FTI that has clinical activity in solid tumors and antileukemic activity in vitro. In a phase I trial of Zarnestra in patients with high-risk leukemia (resistant or relapsed acute myeloid leukemia [AML] or acute lymphocytic leukemia [ALL], chronic myeloid leukemia [CML] in blast crisis, or AML in poor prognosis subgroups), patients experienced an overall response rate of 29%. Zarnestra was well tolerated with no dose-limiting toxicities through doses up to 900 mg twice daily. Assays measuring inhibition of farnesyltransferase activity showed a reliable inhibition at doses greater than 300 mg twice daily, and pharmacokinetic studies indicated that Zarnestra accumulated preferentially in the bone marrow in a dose-dependent fashion. These results suggest that Zarnestra should be studied further in patients with myeloid leukemia.

R115777 is an orally bioavailable farnesyltransferase inhibitor (FTI) that has displayed encouraging activity in patients with acute myeloid leukemia. To determine whether R115777 might exert similar activity in myelofibrosis with myeloid metaplasia (MMM), we evaluated its effects on circulating myeloid progenitor cells from patients with MMM (n=25) using in vitro colony-forming assays. The median R115777 concentrations that inhibited colony formation by 50% were 34 and 2.7 nM for myeloid and megakaryocytic colonies from MMM patients, respectively. Progenitors from normal controls and patients with other myeloproliferative disorders demonstrated similar sensitivity. Since the ras polypeptides are one putative target of FTIs, the potential role of ras effectors was examined by incubating parallel progenitor assays with the phosphatidyl-inositol-3 (PI-3) kinase inhibitor LY294002 and the mitogen-activated protein kinase 1 inhibitor PD98059. MMM progenitor colonies (n=7) were highly sensitive to LY294002 but not to PD98059, implying that the PI-3 kinase pathway may be critical for survival and proliferation of these cells. In addition to indicating that MMM progenitors are sensitive to clinically achievable R115777 concentrations in vitro, these results provide a potential explanation for the thrombocytopenia observed with R115777 during the treatment of other hematologic malignancies.

OBJECTIVE

Ras has been identified as a significant contributor to radiation resistance. This article reviews preclinical and phase I clinical studies that reported on combining inhibition of activated Ras and downstream effectors of Ras with radiotherapy.

METHODS

Transfection studies and RNA interference were used to check the role of the Ras isoforms for intrinsic radiation sensibility. Western blotting was used to control for prenylation inhibition of the respective Ras isoforms and for changes in activity of downstream proteins. Clonogenic assays with human and rodent tumor cell lines served for testing radiosensitivity. In vivo, farnesyltransferase inhibitors (FTIs) and irradiation were used to treat xenograft tumors. Ex vivo plating efficiency measurements, regrowth of tumors, and EF5 staining for detection of hypoxia were endpoints in these studies. Simultaneous treatment with L-778,123 and irradiation was performed in non-small cell lung cancer, head and neck cancer, and pancreatic cancer patients.

RESULTS

Radiation sensitization was achieved in vitro and in vivo blocking the prenylation of Ras proteins in cell lines with Ras activated by mutations or receptor signaling. Among the many Ras downstream pathways the phosphoinositide 3 (PI3) kinase-Akt pathway was identified as a contributor to Ras-mediated radiation resistance. Furthermore, increased oxygenation was observed in xenograft tumors after FTI treatment. Combined treatment in a phase I study was safe and effective.

CONCLUSIONS

The rational combination of FTIs with radiotherapy may improve the clinical results of patients with tumors who bear mutant or receptor-signaling activated Ras.

Several small GTPases of the Ras superfamily have been shown to antagonize TGFbeta signaling in human tumor cell lines. Some of these GTPases are post-translationally modified by farnesylation, a lipid modification catalyzed by farnesyltransferase and required for the proteins to attach to membranes and to function. In this study, we investigated the effect of the farnesyltransferase inhibitor FTI-277 on TGFbeta-regulated cell growth and transcription. Treatment of the human pancreatic tumor cell line, Panc-1, with FTI-277 enhanced the ability of TGFbeta to inhibit both anchorage-dependent and -independent tumor cell growth. FTI-277 also enhanced the ability of TGFbeta to induce transcription, as measured by p3TP-lux reporter activity and collagen synthesis. The enhancement of TGFbeta responses by FTI-277 correlated with the stimulation of transcription and protein expression of type II TGFbeta receptor (TbetaRII). Consequently, FTI-277-treated cells exhibited a higher level of TGFbeta binding to its receptor. Thus, inhibition of protein farnesylation stimulates TbetaRII expression, which leads to increased TGFbeta receptor binding and signaling as well as inhibition of tumor cell growth and transformation.

To determine age-related changes in biologically available testosterone (T) among men in a subsistence society and their relationship to energetic status, T, sex hormone binding globulin (SHBG) and anthropometric measures were compared among nomadic and settled Turkana pastoralists of northern Kenya. Hormonal measures were available for 104 nomadic men and 72 settled men, estimated ages 20-90 years. Comparison of the two subpopulations revealed significantly higher blood T (32.7+/- 15.1 vs. 23.4+/-15.2 nM) and SHBG (53.8+/- 19.5 vs. 39.7+/- 20.nM) but not free testosterone index (FTI) (65.6+/- 39.3 vs.66.3+/- 45.9) among the nomads. Total blood T did not exhibit a significant linear decline with age in either subgroup, while SHBG values showed a significant linear increase among the nomads. When controlled for energetic status, FTI showed a significant decrease with age among the nomads, but not the settled males. Total blood T was negatively associated with waist circumference among the nomads, but not the settled males. FTI showed a marginally significant negative association with waist circumference, suprailiac skinfold, and % body fat among the nomads but no associations with body composition among the settled group. These results add additional evidence that T is related to energetic status under conditions of negative energy balance and suggest that cross-population variation in the slope of age-related declines in free serum T and salivary T may be related to energetic status through the effects of SHBG.

BACKGROUND

Female fertility is an important trait in cattle breeding programs. In the Nordic countries selection is based on a fertility index (FTI). The fertility index is a weighted combination of four female fertility traits estimated breeding values for number of inseminations per conception (AIS), 56-day non-return rate (NRR), number of days from first to last insemination (IFL), and number of days between calving and first insemination (ICF). The objective of this study was to identify associations between sequence variants and fertility traits in Jersey cattle based on 1,225 Jersey sires from Denmark with official breeding values for female fertility traits. The association analyses were carried out in two steps: first the cattle genome was scanned for quantitative trait loci using a sire model for FTI using imputed whole genome sequence variants; second the significant quantitative trait locus regions were re-analyzed using a linear mixed model (animal model) for both FTI and its component traits AIS, NRR, IFL and ICF. The underlying traits were analyzed separately for heifers (first parity cows) and cows (later parity cows) for AIS, NRR, and IFL.

RESULTS

In the first step 6 QTL were detected for FTI: one QTL on each of BTA7, BTA20, BTA23, BTA25, and two QTL on BTA9 (QTL9-1 and QTL9-2). In the second step, ICF showed association with the QTL regions on BTA7, QTL9-2 QTL2 on BTA9, and BTA25, AIS for cows on BTA20 and BTA23, AIS for heifers on QTL9-2 on BTA9, IFL for cows on BTA20, BTA23 and BTA25, IFL for heifers on BTA7 and QTL9-2 on BTA9, NRR for heifers on BTA7 and BTA23, and NRR for cows on BTA23.

CONCLUSIONS

The genome wide association study presented here revealed 6 genomic regions associated with FTI. Screening these 6 QTL regions for the underlying female fertility traits revealed that different female fertility traits showed associations with different subsets of the individual FTI QTL peaks. The result of this study contributed to a better insight into the genetic control of FTI in the Danish Jersey.

BACKGROUND

The clinical utility of an automated lesion tagging module based on catheter stability information (VisiTag) with the CARTO system during atrial fibrillation (AF) ablation remains to be established. We investigated whether VisiTag-guided extensive encircling pulmonary vein isolation (EEPVI) produces durable lesions.

METHODS

The study involved 54 patients undergoing EEPVI for paroxysmal AF. We performed EEPVI guided by the module-generated ablation tags, i.e., "VisiTags," which are point-by-point ablation tags placed on 3D maps. The patients were divided into two groups: those treated under a moderate catheter stability VisiTag setting, i.e., a 3-mm distance limit for at least 5 s and a minimum contact force (CF) of 8 g over 25 % of the set time period with a target force-time integral (FTI) ≥300 g*s (n = 27), and those treated under a strict catheter stability setting, i.e., a 3-mm distance limit for at least 10 s and a minimum CF of 10 g over 50 % of the set time period with a target FTI ≥400 g*s (n = 27).

RESULTS

After EEPVI, adenosine triphosphate-provoked dormant PV conduction was observed in six (22 %) patients in the moderate catheter stability group and in one (4 %) patient in the strict catheter stability group (p = 0.1003); the 12.9-month success rate was 81 % in both groups.

CONCLUSIONS

The strict catheter stability setting for automated lesion tagging together with a target FTI of >400 g*s, vs. the moderate catheter stability setting with a target FTI of >300 g*s, produces less frequent ATP-provoked PV conduction and yields a comparably high mid-term success rate.

The effect of lignin degradation products liberated during chemical hydrolysis of lignocellulosic materials on xylose-to-xylitol bioconversion by Candida guilliermondii FTI 20037 was studied. Two aromatic aldehydes (vanillin and syringaldehyde) were selected as model compounds. A two-level factorial design was employed to evaluate the effects of pH (5.5-7.0), cell concentration (1.0-3.0 g l(-1)), vanillin concentration (0-2.0 g l(-1)) and syringaldehyde concentration (0-2.0 g l(-1)) on this bioprocess. The results showed that in the presence of vanillin or syringaldehyde (up to 2.0 g l(-1)) the cell growth was inhibited to different degrees with a complete inhibition of the yeast growth when the mixture of both (at 2.0 g l(-1) each) was added to the fermentation medium. The xylitol yield was not significantly influenced by vanillin, but was strongly reduced by syringaldehyde, which showed a more pronounced inhibitor effect at pH 7.0. The yeast was also able to convert vanillin and syringaldehyde to the corresponding aromatic acids or alcohols and their formation was dependent of the experimental conditions employed.

The knowledge that Ras was readily prenylated by protein FTase and that the inhibition of this reaction has the ability to revert the transformed phenotype, provided the rationale for the development of FTIs as anticancer drugs. Studies have shown that farnesylation of Ras is the first, obligatory first step in a series of post-translational modifications leading to membrane association, which, in turn, determines the switch from an inactive to an active Ras-GTP bound form. Based on the theorical assumption that preventing Ras farnesylation might result in the inhibition of Ras functions, a range of FTIs have been synthesized. Their biology is fascinating since after substantial investigation and their use in several phase II studies and at least two phase III trials, the exact mechanism of action remains unclear. FTIs can block the farnesylation of several additional proteins, such as RhoB, prelamins A and B, centromere proteins (CENP-E, CENP-F), etc. While the FTIs clearly do not or only partly target Ras, these agents appear to have clinical activity in leukemia and in some solid tumors regardless of their Ras mutational status. Although inhibition of FTase by these compounds has been well documented also in normal tissues, their toxic effects seem to be manageable. However, preliminary results of early Phase II-III studies suggest that the activity of FTIs, as a single-agent, is modest and generally lower than that obtained by standard cytotoxic drugs. Ongoing clinical studies are assessing the role of FTIs for early stage disease or in combination with cytotoxic agents or with other molecular targeted therapies for advanced stage tumors. Further insights in the molecular mechanism of action of FTIs might help in better define their optimal use in combination with standard therapies in the treatment of cancer patients.

Farm to Institution (FTI) programs are one approach to align food service operations with health and sustainability guidelines, such as those recently developed by the U.S. Department of Health and Human Services and General Services Administration. Programs and policies that support sourcing local and regional foods for schools, hospitals, faith-based organizations, and worksites may benefit institutional customers and their families, farmers, the local community, and the economy. Different models of FTI programs exist. On-site farmer's markets at institutions have been promoted on federal government property, healthcare facilities, and private institutions nationwide. Farm to School programs focus on connecting schools with local agricultural production with the goal of improving school meals and increasing intake of fruits and vegetables in children. Sourcing food from local farms presents a number of challenges including cost and availability of local products, food safety, and liability considerations and lack of skilled labor for food preparation. Institutions utilize multiple strategies to address these barriers, and local, state, and federal polices can help facilitate FTI approaches. FTI enables the purchasing power of institutions to contribute to regional and local food systems, thus potentially affecting social, economic, and ecological systems. Local and state food policy councils can assist in bringing stakeholders together to inform this process. Rigorous research and evaluation is needed to determine and document best practices and substantiate links between FTI and multiple outcomes. Nutritionists, public health practitioners, and researchers can help communities work with institutions to develop, implement, and evaluate programs and policies supporting FTI.

BACKGROUND

Ras mutations are among the most common oncogene mutations found in multiple myeloma (MM). Patients with mutated Ras are less likely to respond to chemotherapy and have a shortened median survival. Therefore, targeting Ras farnesylation may be a valuable approach to treatment of MM. R115777 (tipifarnib) is a potent farnesyltransferase inhibitor (FTI) presently undergoing phase II/III clinical trials.

METHODS

We reviewed the preclinical and clinical experience of FTIs as antineoplastic agents and describe their potential role in the treatment of MM.

RESULTS

FTIs are a novel group of agents that selectively inhibit farnesyltransferase, an enzyme responsible for the posttranslational modification of several proteins including Ras. Since Ras is among the most commonly mutated oncogenes associated with cancer, this class of drugs has been evaluated in clinical trials in a diversity of tumors. R115777 has been evaluated in a phase II clinical trial in patients with advanced myeloma and found to be well tolerated. It induced disease stabilization in more than 60% of patients with advanced myeloma.

CONCLUSIONS

The drug selectively targets farnesyltransferase, but this effect did not correlate with disease stabilization, suggesting that these drugs may be targeting a survival pathway independent of Ras processing. Further studies will evaluate the use of FTI in maintenance therapy as well as in combination with other agents in advanced myeloma.

Farnesyl transferase inhibitors (FTIs) exhibit limited cytotoxic effects against human cancer cells, perhaps explaining the limited efficacy of FTIs in clinical trials. Learning how these well-tolerated drugs trigger p53-independent apoptosis in mouse models of cancer might therefore benefit efforts to leverage their utility in clinic. Recent clinical findings indicate that the oncogenic Rho guanine nucleotide exchange factor AKAP13/Lbc is associated with clinical responsiveness, in support of an earlier genetic proof in mice that gain of the geranylgeranylated isoform of RhoB which blocks oncogenic Rho signaling is essential for FTI-induced apoptosis. Here we offer evidence that the RhoB effector mDia is a critical downstream player in this death program. Dominant inhibition of mDia ablated FTI-induced apoptosis but not actin reorganization or growth inhibition, the latter of which has been linked previously to interactions with a RhoB effector kinase pathway that downregulates c-Myc. In nude mice, dominant inhibition of mDia promoted tumor formation and ablated FTI antitumor efficacy. Our findings suggest that the RhoB-mDia pathway is critical for the cell death mechanism engaged by FTI. Further, they suggest that mDia may be important for Rho-dependent survival of oncogenically transformed cells, perhaps driven by AKAP13/Lbc.

Farnesyltransferase inhibitors (FTIs) have been developed as potential anti-cancer agents due to their efficacy in blocking malignant growth in a variety of murine models of human tumors. To that end, we have developed a series of pyridone farnesyltransferase inhibitors with potent in vitro and cellular activity. The synthesis, SAR and biological properties of these compounds will be discussed.