Prognostic role of docetaxel-induced suppression of free testosterone serum levels in metastatic prostate cancer patients.

To date, only few data concerning the biologically active, free form of testosterone (FT) are available in metastatic prostate cancer (mPC) and the impact of FT on disease, therapy and outcome is largely unknown. We retrospectively studied the effect of docetaxel on FT and total testosterone (TT) serum levels in 67 mPC patients monitored between April 2008 and November 2020. FT and TT levels were measured before and weekly during therapy.

Lack of noncanonical RAS mutations in cytogenetically normal acute myeloid leukemia.

Transforming mutations in RAS genes are commonly found in human malignancies, including myeloid leukemias. To investigate the incidence, spectrum, and distribution of activating K- and N-RAS mutations in cytogenetically normal acute myeloid leukemia (CN-AML) patients, 204 CN-AML patients were screened. Activating K- and N-RAS mutations were detected in 3 of 204 (1.

Modulation of anthracycline-induced cytotoxicity by targeting the prenylated proteome in myeloid leukemia cells.

Deregulation of Ras/ERK signaling in myeloid leukemias makes this pathway an interesting target for drug development. Myeloid leukemia cell lines were screened for idarubicin-induced apoptosis, cell-cycle progression, cell-cycle-dependent MAP kinase kinase (MEK-1/2) activation, and Top2 expression. Cell-cycle-dependent activation of MEK/ERK signaling was blocked using farnesyltransferase inhibitor (FTI) BMS-214,662 and dual prenyltransferase inhibitor (DPI) L-778,123 to disrupt Ras signaling.

Carboplatin plus weekly docetaxel as salvage chemotherapy in docetaxel-resistant and castration-resistant prostate cancer.

Background: There is no proven, effective, standard second-line chemotherapy for castration- and docetaxel-resistant prostate cancer (DRPC). Recent data suggest that carboplatin may be effective in combination with docetaxel in this setting; however, the optimal docetaxel/carboplatin-based regimen is still unclear.

Aim Of The Study: We identified 43 consecutive patients with DRPC treated with carboplatin (AUC5 d1) and docetaxel (35 mg/m(2) d1, 8, 15 q4w i.

A tagging-via-substrate approach to detect the farnesylated proteome using two-dimensional electrophoresis coupled with Western blotting.

Prenylation is a post-translational modification critical for the proper function of multiple physiologically important proteins, including small G-proteins, such as Ras. Methods allowing rapid and selective detection of protein farnesylation and geranylgeranylation are fundamental for the understanding of prenylated protein function and for monitoring efficacy of drugs such as farnesyltransferase inhibitors (FTIs). Although the natural substrates for prenyltransferases are farnesyl pyrophosphate and geranylgeranyl pyrophosphate, farnesyltransferase has been shown to incorporate isoprenoid analogues into protein substrates.

Targeting vascular endothelial growth factor (VEGF)-receptor-signaling in renal cell carcinoma.

Metastatic renal cell carcinoma (RCC) is resistant to conventional chemotherapy. Combined data for a variety of immunotherapies resulted in an overall chance of partial (PR) or complete remission (CR) of only 12.9%.

Molecularly targeted therapies in myelodysplastic syndromes and acute myeloid leukemias.

Although there has been significant progress in acute myeloid leukemia (AML) treatment in younger adults during the last decade, standard induction therapy still fails to induce remission in up to 40% of AML patients. Additionally, relapses are common in 50-70% of patients who achieve a complete remission, and only 20-30% of patients enjoy long-term disease-free survival. The natural history of myelodysplastic syndrome (MDS) is variable, with about half of the patients dying from cytopenic complications, and an additional 20-30% transforming to AML.

Combining prenylation inhibitors causes synergistic cytotoxicity, apoptosis and disruption of RAS-to-MAP kinase signalling in multiple myeloma cells.

The high incidence of activating RAS mutations, coupled with accumulating evidence linking RAS to multiple myeloma (MM) pathogenesis, indicate that novel therapies utilising inhibitors of RAS prenylation and signalling may be successful in the management of this disease. While preclinical studies investigating prenylation inhibitors, such as lovastatin, farnesyltransferase inhibitors (FTI) and geranylgeranyltransferase inhibitors (GGTI), have been promising, recent phase I/II clinical trials with FTI R115777 were disappointing, suggesting resistance to FTI monotherapy. To address this issue, the effects of FTI, GGTI and lovastatin alone and in combination were analysed in MM cell lines and primary cells.