Tyrosine kinase inhibitors noncompetitively inhibit MCT8-mediated iodothyronine transport.

CONTEXT: Tyrosine kinase inhibitors (TKI) are used for the treatment of various cancers. Case reports and clinical trials have reported abnormal thyroid function tests (TFT) after treatment with sunitinib, imatinib, sorafenib, dasatinib, and nilotinib. An increased requirement for levothyroxine was reported in thyroidectomized patients during TKI treatment. OBJECTIVE: We hypothesized that abnormal TFT are compatible with inhibition of thyroid hormone (TH) transporters and subsequently reduced pituitary-TH feedback. Monocarboxylate transporter 8 (MCT8) is a TH transmembrane transporter in brain, pituitary, and other organs. MCT8 mutation leads to abnormal TFT in patients and respective mouse models. We tested whether TKI are able to inhibit MCT8-mediated TH uptake into cells. DESIGN: Madin-Darby-canine kidney (MDCK1) cells stably expressing human MCT8 were exposed in vitro to TKI at increasing concentrations, and MCT8-mediated [(125)I]T(3) uptake and efflux were measured. The mode of inhibition was determined. RESULTS: TKI exposure dose-dependently inhibited MCT8-dependent T(3) and T(4) uptake. IC(50) values for sunitinib, imatinib, dasatinib, and bosutinib ranged from 13-38 µm, i.e. similar to the Michaelis-Menten constant K(m) for T(3) and T(4), 4 and 8 µm, respectively. Kinetic experiments revealed a noncompetitive mode of inhibition for all TKI tested. CONCLUSIONS: Partial inhibition by TKI of pituitary or hypothalamic TH feedback may increase TSH or increase the levothyroxine requirement of thyroidectomized patients. It is still possible that other mechanisms contribute to TKI-mediated impairments of TFT, e.g. altered metabolism of TH. Bosutinib was not previously reported to alter TFT.

Omacetaxine mepesuccinate for the treatment of leukemia.

INTRODUCTION: Omacetaxine mepesuccinate, formerly known as homoharringtonine, is a first-in-class cephalotaxine that has experienced phases of increasing and waning interest since its first use in traditional Chinese medicine. With activity being reported in patients with chronic myeloid leukemia (CML) resistant to currently available tyrosine kinase inhibitors, renewed interest has recently been generated. AREAS COVERED: The development of omacetaxine mepesuccinate, with emphasis on synthesis and mode of administration, is addressed. An overview on current clinical results as a single agent or within combination regimens in patients with acute myeloid leukemia (AML) and CML is given. EXPERT OPINION: Omacetaxine mepesuccinate has a unique mode of action and appreciable activity in AML and CML with generally mild nonhematologic toxicity. In patients with AML, results indicate a role within combination regimens in selected, possibly elderly patient populations. In CML, patients with resistance to tyrosine kinase inhibitors, especially due to the T315I mutation, are the most intensively studied. Despite successful results in some patients, single-agent therapy with omacetaxine mepesuccinate has resulted in modest results. However, upfront combination with tyrosine kinase inhibitor represents an attractive option due their differing mechanisms of action.

Nilotinib for the treatment of chronic myeloid leukemia.

The introduction of targeted therapy has revolutionized the treatment of chronic myeloid leukemia (CML). The pivotal role of the Philadelphia chromosome, resulting from the breakpoint cluster region-Abelson (BCR-ABL) translocation, led to the development of imatinib mesylate, a tyrosine kinase inhibitor with significant activity against the BCR-ABL oncoprotein. Unprecedented clinical activity in CML led to rapid approval and established first-line therapy with imatinib mesylate as the standard of care in most patients. However, the occurrence of imatinib resistance or intolerance has sparked the development of newer drugs with increased activity or specificity. Nilotinib is a second-generation tyrosine kinase inhibitor that has been rationally designed on the basis of imatinib. An overview is given on clinical results in imatinib-resistant or -intolerant patients that led to its current approval as second-line therapy for the chronic and accelerated phases of CML. Future studies will address the role of nilotinib as first-line therapy, in combination strategies and in the context of specific BCR-ABL mutations.

Adjuvant chemotherapy with folinic acid and 5-fluorouracil in patients with locally advanced rectal cancer previously treated by preoperative radiochemotherapy and curative tumor resection.

BACKGROUND AND AIMS: The role of postoperative adjuvant chemotherapy in patients with rectal cancer pretreated by preoperative radiochemotherapy (RCT) and curative surgery is still poorly investigated. PATIENTS AND METHODS: We pooled data from both arms of a phase III trial in which patients with locally advanced (T3/4) rectal cancer were randomized to preoperative RCT alone or combined with pelvic radio-frequency hyperthermia. After surgery, R0-resected patients were scheduled to adjuvant chemotherapy with four monthly courses of 50 mg folinic acid (FA) and gradually escalated 5-fluorouracil (5-FU, 350-500 mg/m2, days 1-5). Reasons preventing initiation of chemotherapy and treatment-related toxicities were evaluated. Patients' characteristics and survival parameters were compared between the treated and untreated patient groups. RESULTS: Out of 93 patients, 73 (79%) started adjuvant chemotherapy, whereas 19 (21%) did not, mostly due to perioperative complications and refusal. Chemotherapy-related toxicities were mild to moderate in most cases, but--together with protracted postoperative complications--prevented the intended dose escalation of 5-FU in 71% of patients. Distant-failure-free (p=0.03) and overall survival (p=0.03) were improved in the chemotherapy group, although there was a negative selection of patients with unfavourable characteristics into the untreated patient group. INTERPRETATION/CONCLUSION: Adjuvant chemotherapy using FA and 5-FU can be safely applied to the majority of patients with rectal cancer pretreated by RCT and surgery. Survival data are not suitable to allow far-reaching conclusions, but are in line with suggestions of a favourable effect of adjuvant chemotherapy in these patients.