elastin and Pancreatic-Neoplasms

Locally advanced pancreatic tumours are highly resistant to conventional radiochemotherapy. Here we show that such resistance can be surmounted by an injectable depot of thermally responsive elastin-like polypeptide (ELP) conjugated with iodine-131 radionuclides (

Topics: Albumin-Bound Paclitaxel; Animals; Biopolymers; Brachytherapy; Elastin; Iodine Radioisotopes; Mice; Nanoparticles; Paclitaxel; Pancreatic Neoplasms; Peptides; Tumor Microenvironment

The presence of vessel invasion is considered indicative of a poor prognosis in many malignant tumors. We aimed to compare the sensitivity of elastin stains (van Gieson's and orcein methods) with 2 smooth muscle markers (h-caldesmon and desmin) in gastric, pancreatic, and colorectal adenocarcinoma specimens.. We used 27 (29.3%) gastric, 35 (38.0%) pancreatic, and 30 (32.6%) colorectal resection specimens. We applied a provisional classification of vessel invasion patterns: type A, a focus with a nearby artery unaccompanied by a vein; type T, a focus at the invasive front without an unaccompanied artery; and type X, foci that only appeared by any of the 4 stains used.. There were 369 foci. The smooth muscle markers were more sensitive than the elastin stains, and h-caldesmon more sensitive than desmin, in all types. Among the 139 type A foci, 33 (23.7%) were positive by desmin and h-caldesmon, whereas the elastin stains were not ( P = .001). h-Caldesmon was the only positive marker in 11 (7.9%; P = .011). Among the 78 type T foci, 21 (26.9%) were positive by desmin and h-caldesmon, when both elastin stains were negative ( P = .000). In 16 (20.5%) foci, h-caldesmon was the only positive marker ( P = .002). Among 152 type X foci, 91 (59.9%) were positive by all markers, 26 (17.1%) by both desmin and h-caldesmon, and 9 (5.9%) by only the 2 elastin stains ( P = .001).. We recommend these stains for suspect foci in gastric, pancreatic, and colorectal adenocarcinoma specimens. They might highlight both predictable and unpredictable foci.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Calmodulin-Binding Proteins; Colorectal Neoplasms; Desmin; Elastin; Female; Humans; Immunohistochemistry; Male; Middle Aged; Neovascularization, Pathologic; Pancreatic Neoplasms; Staining and Labeling; Stomach Neoplasms; Young Adult

Intratumoral radiation therapy - 'brachytherapy' - is a highly effective treatment for solid tumors, particularly prostate cancer. Current titanium seed implants, however, are permanent and are limited in clinical application to indolent malignancies of low- to intermediate-risk. Attempts to develop polymeric alternatives, however, have been plagued by poor retention and off-target toxicity due to degradation. Herein, we report on a new approach whereby thermally sensitive micelles composed of an elastin-like polypeptide (ELP) are labeled with the radionuclide (131)I to form an in situ hydrogel that is stabilized by two independent mechanisms: first, body heat triggers the radioactive ELP micelles to rapidly phase transition into an insoluble, viscous coacervate in under 2 min; second, the high energy β-emissions of (131)I further stabilize the depot by introducing crosslinks within the ELP depot over 24h. These injectable brachytherapy hydrogels were used to treat two aggressive orthotopic tumor models in athymic nude mice: a human PC-3 M-luc-C6 prostate tumor and a human BxPc3-luc2 pancreatic tumor model. The ELP depots retained greater than 52% and 70% of their radioactivity through 60 days in the prostate and pancreatic tumors with no appreciable radioactive accumulation (≤ 0.1% ID) in off-target tissues after 72h. The (131)I-ELP depots achieved >95% tumor regression in the prostate tumors (n=8); with a median survival of more than 60 days compared to 12 days for control mice. For the pancreatic tumors, ELP brachytherapy (n=6) induced significant growth inhibition (p=0.001, ANOVA) and enhanced median survival to 27 days over controls.

Topics: Animals; Brachytherapy; Cell Line, Tumor; Delayed-Action Preparations; Elastin; Hot Temperature; Humans; Hydrogels; Injections; Iodine Radioisotopes; Male; Mice, Inbred BALB C; Mice, Nude; Micelles; Pancreas; Pancreatic Neoplasms; Peptides; Phase Transition; Prostate; Prostatic Neoplasms

This work describes the effects of elastin-like polypeptide (ELP) with the p21(Waf1/Cip1)-derived cell cycle inhibitory peptide (p21) on pancreatic tumor cells with gemcitabine. The thermo-responsive property of ELP permits use of a mild, local hyperthermia to target tumors for the transport of chemotherapeutics. In this study, a p21-ELP construct with Bac cell penetrating peptide was designed, and its anticancer activities in pancreatic cancer cell lines was examined. In combination with gemcitabine, the peptide demonstrated enhanced in vitro cytotoxicity as well as tumor growth inhibition in an animal model. Our data suggest that this ELP construct, with gemcitabine, may improve pancreatic cancer therapy.

Topics: Active Transport, Cell Nucleus; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Cell-Penetrating Peptides; Cyclin-Dependent Kinase Inhibitor p21; Deoxycytidine; Dose-Response Relationship, Drug; Elastin; Feasibility Studies; Female; Gemcitabine; Humans; Hypothermia, Induced; Mice; Mice, Nude; Pancreatic Neoplasms; Phosphorylation; Recombinant Fusion Proteins; Retinoblastoma Protein; S Phase Cell Cycle Checkpoints; Time Factors; Xenograft Model Antitumor Assays