Evaluation of safety, pharmacokinetics, and efficacy of vorinostat, a histone deacetylase inhibitor, in the treatment of gastrointestinal (GI) cancer in a phase I clinical trial.

BACKGROUND: Control of epigenetic changes using histone deacetylase inhibitors (HDACi) is thought to be a promising target in therapy of gastrointestinal (GI) cancer. In this study, we evaluated the safety, pharmacokinetics, and efficacy of two dosing regimens of vorinostat, an oral HDACi, in patients with GI tumors. METHODS: Patients received either vorinostat 300 mg bid for 3 consecutive days followed by 4 rest days per cycle (n = 10) or vorinostat 400 mg qd for 21 consecutive days per cycle (n = 6). Pharmacokinetic parameters were assessed for the first treatment cycle. Efficacy was determined through evaluation of tumors and assessment of treatment response. RESULTS: The median treatment duration of 300 mg bid was 52.0 days and of 400 mg qd was 51.5 days. The most common drug-related adverse events were anorexia, nausea, fatigue, and hyperglycemia. Two patients taking 400 mg qd had dose-limiting toxicities (DLTs) of thrombocytopenia. No patients taking 300 mg bid experienced DLT. Five patients taking 300 mg bid and 2 patients taking 400 mg qd maintained stable disease for >8 weeks, with the maximum duration of 245 days. Mean drug exposure (±SD) was generally higher with 400 mg qd (area under the curve [AUC(0-∞)] of 7.75 ± 2.79 µM h on Day 1 post-dose) compared with 300 mg bid (AUC(0-∞) of 3.94 ± 1.56 µM h on Day 1 post-dose). CONCLUSIONS: Vorinostat 300 mg bid for 3 consecutive days followed by 4 days of rest was better tolerated in patients with GI cancer than a higher once daily dose. Additionally, there were patients in both groups who achieved stable disease, most maintaining it for longer than 8 weeks, suggesting vorinostat as a possible active agent in the treatment of GI cancer.

Utility of Physical Examination Findings for Predicting Low-Back Pain in Adolescent Patients with Early-Stage Spondylolysis: A Retrospective Comparative Cohort Study.

INTRODUCTION: This study aimed to elucidate low-back pain (LBP) characteristics, i.e., its qualities, extent, and location, in patients with early-stage spondylolysis (ESS). METHODS: We recruited patients (≤18 years old) who presented with acute LBP lasting up to 1 month. Patients were divided into ESS and nonspecific LBP (NS-LBP) groups based on their magnetic resonance imaging findings; patients showing no pathological findings that might explain the cause of LBP were classified as NS-LBP. All patients were evaluated using the following tests: hyperextension and hyperflexion (pain provocation tests in a standing position), pain quality (sharp/dull), pain extent (fingertip-sized area/palm-sized area), and pain location (left and/or right pain in side [side]/central pain [center]). We have also compared outcomes between the ESS and NS-LBP groups in terms of gender and physical symptoms. RESULTS: Of 101 patients, 53 were determined to have ESS (ESS group: mean age: 14.3 years old; 43 males/10 females), whereas 48 had no pathological findings explaining the LBP origin [NS-LBP group (mean age, 14.4 years old; 31 males/17 females)]. Chi-squared test has identified gender (male), a negative result on hyperflexion test, pain extent (fingertip-sized area), and pain location (side) to be significantly associated with ESS. Among these, regression analysis revealed that male gender and LBP located on the side were significantly associated with ESS (p<0.05). CONCLUSIONS: Although the hyperextension test is generally considered useful for ESS, we demonstrated that its association is not deemed significant. Our results indicate that male gender, a negative result of the hyperflexion test, fingertip-sized pain area, and LBP on the side may be specific characteristics of ESS. Of these physical signs, male gender and LBP located on the side are characteristic factors suggesting ESS presence.

Potential efficacy of the oral histone deacetylase inhibitor vorinostat in a phase I trial in follicular and mantle cell lymphoma.

Vorinostat (suberoylanilide hydroxamic acid, SAHA, Zolinza) is a histone deacetylase inhibitor with clinical activity in cutaneous T-cell lymphoma (CTCL). A phase I trial of oral vorinostat was conducted in Japanese patients with malignant lymphoma. Vorinostat 100 or 200 mg was administered twice daily for 14 consecutive days followed by a 1-week rest interval. Of 10 patients enrolled, four had follicular lymphoma (FL), two mantle cell lymphoma (MCL), two diffuse large B-cell lymphoma, and two CTCL (median age, 60 years; median number of prior regimens, 3). Vorinostat was well tolerated up to 200 mg with only one of six patients developing a dose-limiting toxicity (DLT; Grade 3 anorexia/hypokalemia). Common Grade 3 events were reversible neutropenia (30%), thrombocytopenia, and hypermagnesemia (20% each). The median number of treatment cycles was five (range, 1-36); two patients were continuing treatment. The overall response rate was 40%, with two complete responses/unconfirmed (CRu) and one partial response among FL patients and one CRu among MCL patients. One FL patient maintained CRu for 18.0 months. The median time to achieve CRu among the three patients was 8 months. These data suggest that further investigations of vorinostat in non-Hodgkin lymphoma, focusing on FL and MCL, are warranted.

Phase I and pharmacokinetic study of vorinostat (suberoylanilide hydroxamic acid) in Japanese patients with solid tumors.

Vorinostat (suberoylanilide hydroxamic acid), a potent, oral histone deacetylase inhibitor, has demonstrated clinical activity in non-Japanese patients with various hematological and solid tumors. We sought to determine the maximum tolerated dose and a recommended phase II dose for 18 Japanese patients with solid tumors (median age, 58 years; range, 25-72 years) who failed standard therapy. Patients received vorinostat for 14 days followed by a 7-day rest. The initial dose was 100 mg twice daily escalating by 100 mg twice daily. Once-daily dosing was tested at 400 and 500 mg. A maximum tolerated dose could not be identified. Dose-limiting toxicities (thrombocytopenia, anorexia, and fatigue) were observed in two of six patients receiving 200 mg twice daily and in one of six patients receiving 500 mg once daily. In the 100-500 mg dose range, vorinostat area under the concentration-time curve increased in proportion to dose with a pharmacokinetic profile similar to that established in non-Japanese patients. Vorinostat doses of 200 mg twice daily or 500 mg once daily for 14 days followed by a 7-day rest were well tolerated and are candidate doses for phase II trials, although a maximum tolerated dose for vorinostat was not reached.

Early myelodysplastic syndrome after allogeneic bone marrow transplantation for acute myeloid leukemia.

A 19-year-old male with de novo acute myeloid leukemia (AML) in complete remission received a bone marrow transplant from a HLA-matched donor. Because of major incompatibility for ABO blood type, bone marrow mononuclear cells of the donor were infused after conditioning including total body irradiation (TBI). Engraftment was confirmed on day +23. On day +91, recipient ABO blood genotype was detected in burst forming-unit erythroid (BFU-E) using polymerase chain reaction. Thereafter, myelodysplastic syndrome (MDS) of recipient origin rapidly developed and progressed into a chronic myelomonocytic leukemia-like disorder. An association between MDS and TBI is suggested.

Massive immune hemolysis after non-myeloablative allogeneic peripheral blood stem cell transplantation with minor ABO-incompatibility.

A 35-year-old male, blood group B, Rh(D)+ type, received an allogeneic peripheral blood stem cell (PBSC) transplant after a non-myeloablative regimen of fludarabine and cyclophosphamide for resistant gammadelta cutaneous T-cell lymphoma (CTCL). The donor was his HLA-identical brother, blood group O, Rh(D)+ type. Graft-versus-host disease (GVHD) prophylaxis was performed with cyclosporine alone. On day +8, massive immune hemolysis occurred, followed by acute renal failure. Hemodialysis was performed eight times until recovery of renal function on day +24. The risk of delayed immune hemolysis after non-myeloablative allogeneic PBSC transplantation with minor ABO-incompatibility must be considered.

[Acute promyelocytic leukemia accompanied by retinoic acid syndrome with complications of acute myocardial infarction and cerebral infarction during treatment with all-trans retinoic acid].

A 71-year-old man visited our hospital complaining of fever and a bleeding tendency. The peripheral blood WBC count was 10,400/microliter with 90% promyelocytes. The bone marrow was hypercellular with 88% promyelocytes. Disseminated intravascular coagulation was recognized. The patient was diagnosed as having acute promyelocytic leukemia and was treated with daily oral administration of all-trans retionic acid (ATRA) (45 mg/m2/day) and cytarabine (160 mg/day, intravenous drip infusion for the initial five days). The ATRA treatment induced leukemic cells to undergo mature myeloid differentiation. On day 24 after the start of treatment, the WBC count rapidly increased and acute myocardial infarction appeared, with consciousness disturbance and bilateral Babinski reflex appearing three hours later. Magnetic resonance imaging showed a fresh lacunar infarction of the right lenticular nucleus, and serum levels of IL-6 and PAI-1 were found to be elevated at the onset of infarction. Since there was a possibility that the retinoic acid syndrome (RAS) might have helped bring about the infarctions, we stopped the ATRA treatment and started administration of methyl-prednisolone (500 mg/body/day for 3 days) and gabexate mesilate. The WBC count decreased immediately and the consciousness disturbance improved. In this case, ATRA treatment might have initiated the RAS and resulted in some endothelial damage, thus causing the infarctions.

Fanconi anemia protein complex is a novel target of the IKK signalsome.

Fanconi anemia (FA), a genetic disorder predisposing to aplastic anemia and cancer, is characterized by hypersensitivity to DNA-damaging agents and oxidative stress. Five of the cloned FA proteins (FANCA, FANCC, FANCE, FANCF, FANCG) appear to be involved in a common functional pathway that is required for the monoubiquitination of a sixth gene product, FANCD2. Here, we report that FANCA associates with the IkappaB kinase (IKK) signalsome via interaction with IKK2. Components of the FANCA complex undergo rapid, stimulus-dependent changes in phosphorylation, which are blocked by kinase-inactive IKK2 (IKK2 K > M). When exposed to mitomycin C, cells expressing IKK2 K > M develop a cell cycle abnormality characteristic of FA. Thus, FANCA may function to recruit IKK2, thus providing the cell a means of rapidly responding to stress.

Phosphorylation of Fanconi anemia protein, FANCA, is regulated by Akt kinase.

Phosphorylation of the Fanconi anemia complementation group A (FANCA) protein is thought to be important for the function of the FA pathway. However, the kinase for FANCA (so-called FANCA-PK) remains to be identified. FANCA has a consensus sequence for Akt kinase near serine 1149 (Ser1149), suggesting that Akt can phosphorylate FANCA. We performed in vitro kinase assays using as substrate either a GST-fusion wild-type (WT) FANCA fragment or a GST-fusion FANCA fragment containing a mutation from serine to alanine at 1149 (FANCA-S1149A). These experiments confirmed that FANCA is phosphorylated at Ser 1149, in vitro. However, (32)P-orthophosphate labeling experiments revealed that FANCA-S1149A was more efficiently phosphorylated than WT-FANCA. Furthermore, phosphorylation of wild-type FANCA was blocked by coexpression of a constitutively active (CA)-Akt and enhanced by a dominant-negative (DN) Akt. Our results suggest that Akt is a negative regulator of FANCA phosphorylation.