A new survival model for hyperthermic intraperitoneal chemotherapy (HIPEC) in tumor-bearing rats in the treatment of peritoneal carcinomatosis

BACKGROUND: Cytoreduction followed by hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival in patients with peritoneal carcinomatosis of colorectal origin. Animal models are important in the evaluation of new treatment modalities. The purpose of this study was to devise an experimental setting which can be routinely used for the investigation of HIPEC in peritoneal carcinomatosis. METHODS: A new peritoneal perfusion system in tumor bearing rats were tested. For this purpose CC531 colon carcinoma cells were implanted intraperitoneally in Wag/Rija rats. After 10 days of tumor growth the animals were randomized into three groups of six animals each: group 1: control (n = 6), group 2: HIPEC with mitomycin C in a concentration of 15 mg/m(2 )(n = 6), group III: mitomycin C i.p. as monotherapy in a concentration of 10 mg/m(2 )(n = 6). After 10 days, total tumor weight and the extent of tumor spread, as classified by the modified Peritoneal Cancer Index (PCI), were assessed by autopsy of the animals. RESULTS: No postoperative deaths were observed. Conjunctivitis, lethargy and loss of appetite were the main side effects in the HIPEC group. No severe locoregional or systemic toxity was observed. All control animals developed massive tumor growth. Tumor load was significantly reduced in the treatment group and was lowest in group II. CONCLUSION: The combination of hyperthermia with MMC resulted in an increased tumoricidal effect in the rat model. The presented model provides an opportunity to study the mechanism and effect of hyperthermic intraperitoneal chemotherapy and new drugs for this treatment modality

Toxicity and morbility after isolated lower limb perfusion in 242 chemo-hyperthermal treatments for cutaneous melanoma: The experience of the Tuscan Reference Centre

<p>Abstract</p> <p>Background</p> <p>The aim of this retrospective study was to assess the results concerning the regional and systemic toxicity and complications in 242 chemo-hyperthermal treatments (HILPs) for lower limb melanoma.</p> <p>Patients and methods</p> <p>60 HILPs (G-A) were performed with mild HT plus L-PAM (10 mg/lt) ± D-actimomycin; 74 HILPs (G-B) with true HT (40–41.8°C) plus L-PAM (10 mg/lt) ± D-act; 108 HILPs (G-C) with true HT plus L-PAM (10 mg/lt) ± D-act plus L-PAM (5 mg/lt) additional bolus.</p> <p>Results</p> <p>Limb toxicity was very low in G-A and in G-B; increasing toxicity (grade III = 37%) in G-C; no grade IV statistical difference was registered in all three groups, with percentage values among 1.6% and 2.7%. Systemic toxicity showed itself only in the haemopoietic parameters. No differences were registered in G-B vs G-A group. In G-C vs G-B a significative increase of systemic toxicity was seen in grade 3 (p < 0.05). Postoperative complications were acceptable. Local and systemic side-effects were transient; no permanent neurological limb deficit was registered. The postoperative mortality was recorded in 3/182 HILPs (1.6%) of the G-B and G-C groups.</p> <p>Conclusion</p> <p>These data suggested that the technical implementations reduced the occurrence and the severity of the side effects and complications. The essential requirement for HILP is the quality assurance of the procedures. Although higher regional and systemic toxicity were observed in the G-C group caused by L-PAM additional bolus, the safeness of the procedures under the true hyperthermal regimen and the time increase of the high L-PAM concentration have assured the treatment reliability along with the increased clinical efficacy expectations of the treatments.</p

A Novel Docetaxel-Loaded Poly (ε-Caprolactone)/Pluronic F68 Nanoparticle Overcoming Multidrug Resistance for Breast Cancer Treatment

Multidrug resistance (MDR) in tumor cells is a significant obstacle to the success of chemotherapy in many cancers. The purpose of this research is to test the possibility of docetaxel-loaded poly (ε-caprolactone)/Pluronic F68 (PCL/Pluronic F68) nanoparticles to overcome MDR in docetaxel-resistance human breast cancer cell line. Docetaxel-loaded nanoparticles were prepared by modified solvent displacement method using commercial PCL and self-synthesized PCL/Pluronic F68, respectively. PCL/Pluronic F68 nanoparticles were found to be of spherical shape with a rough and porous surface. The nanoparticles had an average size of around 200 nm with a narrow size distribution. The in vitro drug release profile of both nanoparticle formulations showed a biphasic release pattern. There was an increased level of uptake of PCL/Pluronic F68 nanoparticles in docetaxel-resistance human breast cancer cell line, MCF-7 TAX30, when compared with PCL nanoparticles. The cytotoxicity of PCL nanoparticles was higher than commercial Taxotere®in the MCF-7 TAX30 cell culture, but the differences were not significant (p > 0.05). However, the PCL/Pluronic F68 nanoparticles achieved significantly higher level of cytotoxicity than both of PCL nanoparticles and Taxotere®(p < 0.05), indicating docetaxel-loaded PCL/Pluronic F68 nanoparticles could overcome multidrug resistance in human breast cancer cells and therefore have considerable potential for treatment of breast cancer

A mouse model for triple-negative breast cancer tumor-initiating cells (TNBC-TICs) exhibits similar aggressive phenotype to the human disease

<p>Abstract</p> <p>Background</p> <p>Triple-negative breast cancer (TNBC) exhibit characteristics quite distinct from other kinds of breast cancer, presenting as an aggressive disease--recurring and metastasizing more often than other kinds of breast cancer, without tumor-specific treatment options and accounts for 15% of all types of breast cancer with higher percentages in premenopausal African-American and Hispanic women. The reason for this aggressive phenotype is currently the focus of intensive research. However, progress is hampered by the lack of suitable TNBC cell model systems.</p> <p>Methods</p> <p>To understand the mechanistic basis for the aggressiveness of TNBC, we produced a stable TNBC cell line by sorting for 4T1 cells that do not express the estrogen receptor (ER), progesterone receptor (PgR) or the gene for human epidermal growth factor receptor 2 (HER2). As a control, we produced a stable triple-positive breast cancer (TPBC) cell line by transfecting 4T1 cells with rat HER2, ER and PgR genes and sorted for cells with high expression of ER and PgR by flow cytometry and high expression of the HER2 gene by Western blot analysis.</p> <p>Results</p> <p>We isolated tumor-initiating cells (TICs) by sorting for CD24⁺/CD44^high/ALDH1⁺cells from TNBC (TNBC-TICs) and TPBC (TPBC-TICs) stable cell lines. Limiting dilution transplantation experiments revealed that CD24⁺/CD44^high/ALDH1⁺cells derived from TNBC (TNBC-TICs) and TPBC (TPBC-TICs) were significantly more effective at repopulating the mammary glands of naïve female BALB/c mice than CD24^-/CD44^-/ALDH1^-cells. Implantation of the TNBC-TICs resulted in significantly larger tumors, which metastasized to the lungs to a significantly greater extent than TNBC, TPBC-TICs, TPBC or parental 4T1 cells. We further demonstrated that the increased aggressiveness of TNBC-TICs correlates with the presence of high levels of mouse twenty-five kDa heat shock protein (Hsp25/mouse HspB1) and seventy-two kDa heat shock protein (Hsp72/HspA1A).</p> <p>Conclusions</p> <p>Taken together, we have developed a TNBC-TICs model system based on the 4T1 cells which is a very useful metastasis model with the advantage of being able to be transplanted into immune competent recipients. Our data demonstrates that the TNBC-TICs model system could be a useful tool for studies on the pathogenesis and therapeutic treatment for TNBC.</p

The expression of HSP60 and HSP10 in large bowel carcinomas with lymph node metastase

BACKGROUND: The involvement of Heat Shock Proteins (HSP) in cancer development and progression is a widely debated topic. The objective of the present study was to evaluate the presence and expression of HSP60 and HSP10 in a series of large bowel carcinomas and locoregional lymph nodes with and without metastases. METHODS: 82 Astler and Coller's stage C2 colorectal cancers, of which 48 well-differentiated and 34 poorly-differentiated, were selected along with 661 lymph nodes, including 372 with metastases and 289 with reactive hyperplasia only, from the same tumours. Primitive tumours and both metastatic and reactive lymph nodes were studied; specifically, three different compartments of the lymph nodes, secondary follicle, paracortex and medullary sinus, were also analysed. An immunohistochemical research for HSP60 and HSP10 was performed and the semiquantitative results were analysed by statistical analysis to determine the correlation between HSPs expression and 1) tumour grading; 2) degree of inflammation; 3) number of lymph nodes involved; 4) lymph node compartment hyperplasia. Moreover, western blotting was performed on a smaller group of samples to confirm the immunohistochemical results. RESULTS: Our data show that the expression of HSP60, in both primary tumour and lymph node metastasis, is correlated with the tumoral grade, while the HSP10 expression is not. Nevertheless, the levels of HSP10 are commonly higher than the levels of HSP60. In addition, statistical analyses do not show any correlation between the degree of inflammation and the immunopositivity for both HSP60 and HSP10. Moreover, we find a significant correlation between the presence of lymph node metastases and the positivity for both HSP60 and HSP10. In particular, metastatic lymph nodes show a higher percentage of cells positive for both HSP60 and HSP10 in the secondary follicles, and for HSP10 in the medullary sinuses, when compared with hyperplastic lymph nodes. CONCLUSION: HSP60 and HSP10 may have diagnostic and prognostic significance in the management of this tumour and their overexpression in tumoral cells may be functionally related to tumoral progression. We hypothesise that their expression in follicular and medullary cells of lymph nodes may be induced by formation of metastases. Further studies based on these observations could lead to a better understanding of the HSPs involvement in colorectal cancer progression, as well as other neoplasms