Pancreatic Ductal Adenocarcinoma (PDAC) circulating tumor cells influence myeloid cell differentiation to support their survival and immunoresistance in portal vein circulation.

The portal venous circulation provides a conduit for pancreatic ductal adenocarcinoma (PDAC) tumor cells to the liver parenchyma sinusoids, a frequent site of metastasis. Turbulent flow in the portal circulation promotes retention of PDAC shed circulating tumor cells (CTC) and myeloid-derived immunosuppressor cells (MDSC). Excessive colony stimulating factor-1 receptor (CSF1R) signaling can induce myeloid differentiation to MDSC and transformation of MDSC to myeloid-derived fibroblasts (M-FB).

A Novel Polyamine-Targeted Therapy for BRAF Mutant Melanoma Tumors.

Mutant serine/threonine protein kinase B-Raf (BRAF) protein is expressed in over half of all melanoma tumors. Although BRAF inhibitors (BRAFi) elicit rapid anti-tumor responses in the majority of patients with mutant BRAF melanoma, the tumors inevitably relapse after a short time. We hypothesized that polyamines are essential for tumor survival in mutant BRAF melanomas.

Investigation of Polyamine Metabolism and Homeostasis in Pancreatic Cancers.

Pancreatic cancers are currently the fourth leading cause of cancer-related death and new therapies are desperately needed. The most common pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). This report describes the development of therapies, which effectively deplete PDAC cells of their required polyamine growth factors.

ATP13A3 and caveolin-1 as potential biomarkers for difluoromethylornithine-based therapies in pancreatic cancers.

The purpose of this paper was to better understand the role of polyamine transport in pancreatic cancers.This paper identifies potential biomarkers for assessing the relative tumor commitment to polyamine biosynthesis or transport. Cell lines with low polyamine import activity and low ATP13A3 protein levels appear committed to polyamine biosynthesis and required high concentrations of the polyamine biosynthesis inhibitor, difluoromethylornithine (DFMO) to inhibit their growth (e.

Designing the polyamine pharmacophore: influence of N-substituents on the transport behavior of polyamine conjugates.

N-Ethylated N-arylmethyl polyamine conjugates were synthesized and evaluated for their ability to target the polyamine transporter (PAT). To understand the effect of N-ethylation upon PAT selectivity, ethyl groups were appended onto a PAT-selective N (1)-anthracenenylmethyl homospermidine derivative, 1b. Bioevaluation in L1210 murine leukemia cells and in two Chinese hamster ovary cell lines (PAT-active CHO and PAT-deficient CHO-MG) revealed a dramatic decrease in PAT targeting ability upon N (1) or N (5) ethylation of the pharmacophore 1b.

Lipopolyamine treatment increases the efficacy of intoxication with saporin and an anticancer saporin conjugate.

Saporin is a type I ribosome-inactivating protein that is often appended with a cell-binding domain to specifically target and kill cancer cells. Urokinase plasminogen activator (uPA)-saporin, for example, is an anticancer toxin that consists of a chemical conjugate between the human uPA and native saporin. Both saporin and uPA-saporin enter the target cell by endocytosis and must then escape the endomembrane system to reach the cytosolic ribosomes.

Defining the molecular requirements for the selective delivery of polyamine conjugates into cells containing active polyamine transporters.

Several N(1)-substituted polyamines containing various spacer units between nitrogen centers were synthesized as their respective HCl salts. The N(1)-substituents included benzyl, naphthalen-1-ylmethyl, anthracen-9-ylmethyl, and pyren-1-ylmethyl. The polyamine spacer units ranged from generic (4,4-triamine, 4,3-triamine, and diaminooctane) spacers to more exotic [2-(ethoxy)ethanoxy-containing diamine, hydroxylated 4,3-triamine, and cyclohexylene-containing triamine] spacers.

Synthesis and characterization of N(1)-(4-toluenesulfonyl)-N(1)- (9-anthracenemethyl)triamines.

A modular synthetic approach was developed to access triamines with varying tether lengths from commercially available aminoalkanols. Initial N-alkylation via reductive amination with anthracene-9-carbaldehyde provided the secondary amines in good yield. Subsequent ditosylation with excess TsCl yielded the respective bis-N,O-tosylates.

An Improved Synthesis of O-Benzoyl Protected Hydroxamates.

Several primary amines (R-NH(2)) were converted to their corresponding O-benzoyl protected hydroxamates under biphasic conditions. The intermediate (benzoyloxy)amines (R-NHOCOPh) were generated using benzoyl peroxide dissolved in CH(2)Cl(2) and an aqueous carbonate buffer (pH 10.5) at room temperature.