Phase I and pharmacokinetic study of 3'-C-ethynylcytidine (TAS-106), an inhibitor of RNA polymerase I, II and III,in patients with advanced solid malignancies.

BACKGROUND: TAS-106 is a novel nucleoside analog that inhibits RNA polymerases I, II and II and has demonstrated robust antitumor activity in a wide range of models of human cancer in preclinical studies. This study was performed to principally evaluate the feasibility of administering TAS-106 as a bolus intravenous (IV) infusion every 3 weeks. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of TAS-106 as a single bolus IV infusion every 3 weeks. Plasma and urine sampling were performed during the first course to characterize the pharmacokinetic profile of TAS-106 and assess pharmacodynamic relationships. RESULTS: Thirty patients were treated with 66 courses of TAS-106 at eight dose levels ranging from 0.67-9.46 mg/m(2). A cumulative sensory peripheral neuropathy was the principal dose-limiting toxicity (DLT) of TAS-106 at the 6.31 mg/m(2) dose level, which was determined to be the maximum tolerated dose (MTD). Other mild-moderate drug-related toxicities include asthenia, anorexia, nausea, vomiting, myelosuppression, and dermatologic effects. Major objective antitumor responses were not observed. The pharmacokinetics of TAS-106 were dose-proportional. The terminal elimination half-life (t(1/2)) averaged 11.3 ± 3.3 h. Approximately 71% of TAS-106 was excreted in the urine as unchanged drug. Pharmacodynamic relationships were observed between neuropathy and: C(5min;) AUC(0-inf;) and dermatologic toxicity. CONCLUSIONS: The recommended phase II dose of TAS-106 is 4.21 mg/m(2). However, due to a cumulative drug-related peripheral sensory neuropathy that proved to be dose-limiting, further evaluation of this bolus every 21 day infusion schedule will not be pursued and instead, an alternate dosing schedule of TAS-106 administered as a continuous 24-hour infusion will be explored to decrease C(max) in efforts to minimize peripheral neuropathy and maximize antitumor activity.

Diverging functions among calreticulin isoforms in higher plants.

The ER chaperone calreticulin plays vital roles in numerous cellular processes, including Ca2+-homeostasis, apoptosis, and cell adhesion, in animal cells. Although calreticulin has been systematically characterized in animal cells, the focus has been on one of the isoforms. However, recent advances in the plant calreticulin field have revealed functional divergence of calreticulin isoforms. While two of the plant isoforms appear to work within a general ER chaperone framework, the third isoform is associated with folding of receptors for brassinosteroids and bacterial peptides. Hence, the discovery of functional specialization of plant calreticulins opens up new vistas for calreticulins also in the animal field.

Higher plant calreticulins have acquired specialized functions in Arabidopsis.

BACKGROUND: Calreticulin (CRT) is a ubiquitous ER protein involved in multiple cellular processes in animals, such as protein folding and calcium homeostasis. Like in animals, plants have evolved divergent CRTs, but their physiological functions are less understood. Arabidopsis contains three CRT proteins, where the two CRTs AtCRT1a and CRT1b represent one subgroup, and AtCRT3 a divergent member. METHODOLOGY/PRINCIPAL FINDINGS: Through expression of single Arabidopsis family members in CRT-deficient mouse fibroblasts we show that both subgroups have retained basic CRT functions, including ER Ca2+-holding potential and putative chaperone capabilities. However, other more general cellular defects due to the absence of CRT in the fibroblasts, such as cell adhesion deficiencies, were not fully restored. Furthermore, in planta expression, protein localization and mutant analyses revealed that the three Arabidopsis CRTs have acquired specialized functions. The AtCRT1a and CRT1b family members appear to be components of a general ER chaperone network. In contrast, and as recently shown, AtCRT3 is associated with immune responses, and is essential for responsiveness to the bacterial Pathogen-Associated Molecular Pattern (PAMP) elf18, derived from elongation factor (EF)-Tu. Whereas constitutively expressed AtCRT1a fully complemented Atcrt1b mutants, AtCRT3 did not. CONCLUSIONS/SIGNIFICANCE: We conclude that the physiological functions of the two CRT subgroups in Arabidopsis have diverged, resulting in a role for AtCRT3 in PAMP associated responses, and possibly more general chaperone functions for AtCRT1a and CRT1b.

Cutaneous reactions related to systemic immunomodulators and targeted therapeutics.

The arrival of targeted therapeutics into the oncology clinic, while enthusiastically anticipated, introduced the oncologist to dermatologic events that can pose challenging management issues. The dermatologic effects of these targeted agents appear to be more frequent than those with cytotoxic therapy and are not uniform; that is, different agents have distinct dermatologic toxicities. Interestingly, dermatologic toxicity may correlate with antitumor activity with some of these targeted agents. The correlation of rash with response and survival in particular mandates the development of effective and appropriate management strategies. The nature and challenges of the dermatologic events observed to date with epidermal growth factor receptor inhibitors, multikinase inhibitors, proteosome inhibitors, BCR-ABL tyrosine kinase inhibitors, and immunomodulatory drugs will be addressed in this review.

Phase I and pharmacokinetic study of pemetrexed with high-dose folic acid supplementation or multivitamin supplementation in patients with locally advanced or metastatic cancer.

PURPOSE: This phase I study evaluated the effect of folate supplementation on the toxicity, tolerability, and pharmacokinetics of pemetrexed in patients with locally advanced or metastatic cancer. It also examined two different types of vitamin supplementation and whether the extent of prior myelosuppressive therapy affected pemetrexed tolerability. PATIENTS AND METHODS: Patients received a 10-min infusion of 600 to 14,00 mg/m(2) pemetrexed every 3 weeks. Patients were stratified into cohorts by pretreatment status [lightly pretreated (LPT) or heavily pretreated (HPT)] and were supplemented with intermittent high-dose folic acid (HDFA) or with continuous daily multivitamins (MVI) containing nutritional doses of folic acid. Pemetrexed plasma pharmacokinetics were evaluated for cycle 1. RESULTS: Sixty-two HDFA patients (28 HPT and 34 LPT) were treated with 204 cycles of pemetrexed, and 43 MVI patients (20 HPT and 23 LPT) were treated with 182 cycles. Hematologic dose-limiting toxicities included grade 4 neutropenia (5 of 105 patients), grade 4 thrombocytopenia (4 of 105 patients), and febrile neutropenia (3 of 105 patients). Nonhematologic toxicities included fatigue, vomiting, diarrhea, and nausea. Pemetrexed doses of 800 and 1,050 mg/m(2) were well tolerated when administered with vitamin supplementation to HPT and LPT patients, respectively. There were no clinically relevant differences in toxicities or pemetrexed pharmacokinetics for LPT versus HPT patients or for patients receiving HDFA versus daily MVI supplementation. CONCLUSIONS: The pemetrexed doses tolerated in this study with vitamin supplementation were significantly higher than those tolerated in earlier studies without supplementation, and toxicities were independent of the type of vitamin supplementation or prior myelosuppressive treatment. The recommended dose of pemetrexed is 1,050 mg/m(2) in LPT patients and 800 mg/m(2) in HPT patients, irrespective of the type of vitamin supplementation.

Systemic therapeutic options in thymic malignancies: a glimmer of hope.

Progress in the systemic therapy of thymic malignancies has been hampered in the past by the rarity of this disease entity and the lack of a global collaborative effort in conducting phase II studies. Cisplatin-based therapy has been considered the standard of care, though data typically has been derived from a retrospective case-series approach. However, the arrival of novel cytotoxic agents and molecularly targeted agents into the clinic has helped provide the impetus for improved methodology in thymic malignancy research with an emphasis on more prospective phase II studies. This review discusses the results of traditional cytotoxic agents, novel cytotoxic agents, biologic therapy and the initial evaluation of molecularly targeted therapeutics, such as epidermal growth factor receptor inhibitors, for the treatment of thymic malignancies. In addition, potential novel targets such as VEGF, Bcl-2 and c-KIT are assessed.