No abstract

R115777 is a nonpeptidomimetic enzymespecific inhibitor of farnesyl protein transferase (FT) that was developed as a potential inhibitor of Ras protein signaling, with antitumor activity in preclinical models. This study was a phase 1 trial of orally administered R115777 in 35 adults with poor-risk acute leukemias. Cohorts of patients received R115777 at doses ranging from 100 mg twice daily (bid) to 1200 mg bid for up to 21 days. Dose-limiting toxicity occurred at 1200 mg bid, with central neurotoxicity evidenced by ataxia, confusion, and dysarthria. Non-dose-limiting toxicities included reversible nausea, renal insufficiency, polydipsia, paresthesias, and myelosuppression. R115777 inhibited FT activity at 300 mg bid and farnesylation of FT substrates lamin A and HDJ-2 at 600 mg bid. Extracellular signal-regulated kinase (ERK), an effector enzyme of Ras-mediated signaling, was detected in its phosphorylated (acti- vated IntroductionAdult acute leukemias remain formidable therapeutic challenge. Only 70% of adults with newly diagnosed acute myelogenous leukemias (AMLs) achieve complete remission (CR) after cytotoxic induction chemotherapy. Although these CRs may be prolonged in 35% to 40% of younger adults (age Ͻ 60), 1-5 the remainder have a relapse and die. Certain subgroups, including older adults, 3,5,6 patients with AMLs linked to environmental or occupational exposures (including therapy-induced AMLs), and patients with previous myelodysplasia (MDS) or other antecedent hematologic disorders, 7,8 have extremely poor outcomes, with CR rates of 40% or less, CR durations less than 12 months, and cure rates less than 10% to 15%. 3,5,6 The overall outlook for adult acute lymphoblastic leukemias (ALLs) is similar, 9-11 with a particularly poor prognosis in Philadelphia chromosome (Ph ϩ ) disease. 9,12 Thus, new approaches are needed to improve the outcome for adults with refractory leukemias.Improved understanding of signal transduction pathways has resulted in identification of a panoply of potential therapeutic targets. [13][14][15][16] Among these are the membrane-associated G proteins encoded by the ras family of proto-oncogenes. Ras proteins are activated downstream of protein tyrosine kinases (PTKs, eg, growth factor receptors) and, in turn, trigger a cascade of phosphorylation events through sequential activation of Raf, MEK-1, and ERKs (extracellular signal-related kinases). These events are critical to survival of hematopoietic cells. [16][17][18][19] The Ras proteins are synthesized as cytosolic precursors that must attach to the cell membrane to transmit signals. Membrane attachment depends on the addition of a 15-carbon farnesyl group to Ras, a reaction that is catalyzed by the enzyme farnesyltransferase (FT). [20][21][22] FT inhibitors (FTIs) were developed on the premise that FT inhibition would prevent Ras processing and, therefore, transduction of proliferative signals. [22][23][24] Subsequent studies, however, have suggested that the cytotoxic actions of FTIs might also involve other farnesylated ...

R115777 is bioavailable after oral administration and has an acceptable toxicity profile. Based upon pharmacokinetic data, the recommended dose for phase II trials is 500 mg orally bid (total daily dose, 1, 000 mg) for 5 consecutive days followed by 9 days of rest. Studies of continuous dosing and studies of R115777 in combination with chemotherapy are ongoing.

Single agent R115777, given at this dose and schedule, has an acceptable toxicity profile, but does not improve overall survival compared to best supportive care alone in refractory advanced CRC.

Background: Farnesyl protein transferase inhibitors (FTIs) were originally developed to inhibit oncogenic ras, however it is now clear that there are several other potential targets for this drug class. The FTI tipifarnib (ZARNESTRA™, R115777) has recently demonstrated clinical responses in adults with refractory and relapsed acute leukemias. This study was conducted to identify genetic markers and pathways that are regulated by tipifarnib in acute myeloid leukemia (AML).

Sentinel lymph node (SLN) status is highly predictive of overall axillary lymph node involvement in breast cancer. Historically, SLN-positive patients have undergone axillary lymph node dissection in a second surgery. Intraoperative SLN analysis could reduce the cost and complications of a second surgery; however, existing histopathological methods lack standardization and exhibit poor sensitivity. Rapid molecular methods may lead to improved intraoperative diagnosis of SLN metastasis. In this study, we used a genome-wide gene expression analysis of breast and other tissues to identify seven putative markers for detecting breast cancer metastasis. We assessed the utility of these markers for identifying clinically actionable metastases in lymph nodes through reverse transcriptase-polymerase chain reaction analysis of SLNs from 254 breast cancer patients. Polymerase chain reaction signals were compared to pathology on a per-patient basis. The optimal two-gene combination, mammaglobin and cytokeratin 19, detected clinically actionable metastasis in breast SLNs with 90% sensitivity and 94% specificity. Application of stringent criteria for identifying presumptive hematoxylin-and eosin-positive samples increased sensitivity and specificity to 91 and 97%, respectively. This study represents the first comprehensive demonstration of the utility of gene expression markers for detecting clinically actionable breast metastases. An intraoperative molecular assay using these markers has the potential to significantly reduce second surgeries for patients undergoing SLN dissection. Breast cancer is second only to lung cancer in mortality among women worldwide.1 In the care of this significant disease, the evaluation of blood, bone marrow, and lymph nodes for the presence of metastatic cells is an important component of disease characterization and management.2-6 The method for assessment of these peripheral tissues is largely dependent on histological and cytological methods. Detection of metastasis in lymph nodes is typically accomplished by hematoxylin and eosin (H&E) and antibody staining of lymph node sections.7,8 Analysis of bone marrow samples, although still in development, currently involves antibody staining of cytological smears. For some time, there has been discussion about the potential for the use of molecular biological tools to supplement or to improve existing methods.9 Molecular methods such as reverse transcriptase-polymerase chain reaction (RT-PCR) offer increased analytical sensitivity compared with standard histological methods. 10 -12 In addition, nucleic acid-based detection methods such as real-time PCR offer the potential of rapid and sensitive point-of-care testing and the application of objective quantitative assay cut-offs.A clear intersection between these features is the intraoperative assessment of sentinel lymph nodes (SLNs) for the presence of clinically actionable metastasis, a level of metastasis that would be expected to consistently lead to a subsequent axillary lymph node (ALN) dissecti...

No abstract

SUMMARY Acid spring effluents are often covered with mats of the eucaryotic phycocyanin‐containing alga. Cyanidium caldarium. The primary bacterial component of such mats is an acidophilic strain of Bacillus coagulans, and the primary fungal component is Dactylaria gallopava. Because of the limited species diversity, C. caldarium mats appeared to be an excellent system for studying algal excretion and various microbial interactions in nature. From 2 to 6% of the NaH14CO3 taken up by natural or laboratory populations of the alga was excreted as 14C‐labeled materials. The maximum excretion occurred at temperature, light, and pH values optimum for NaH14CO3 uptake. However, when excretion was expressed as a percentage of NaH14CO3 uptake, a higher percentage of the radioactivity was excreted at nonoptimal conditions for NaH14CO3 uptake. Fungal biomass was directly proportional to algal density, but bacterial numbers varied widely and did not correlate with algal numbers. The bacterial and fungal components could be grown in mixed culture with either growing C. caldarium cultures or in an extract prepared, by healing algal cells.