Ciência e terapia do câncer

Modification of the tumor microenvironment by inflammatory cells represents a newly recognized driving force in cancer with critical roles in tumor invasion, growth, angiogenesis, and metastasis. Increased thrombolytic cascade serine proteases, specifically urokinase-type plasminogen activator and its receptor, correlate with inflammatory cell migration, pancreatic cancer growth, invasion and unfavorable outcomes. Inflammation in pancreatic cancer is linked with myeloid-derived suppressor cell (MDSC) activity and cancer progression. Myxomavirus is a complex DNA virus encoding highly potent immune modulators. Serp-1 and M-T7 are two such secreted anti-inflammatory myxomaviral proteins. Serp-1 inhibits uPA, plasmin and coagulation factor X while M-T7 inhibits C, CC, and CXC chemokines. We have explored the potential use of these viral proteins for treatment of a range of human cancer isolates engrafted in severe combined immunodeficient (SCID) mice. Engrafted tumors were treated with either Serp-1, neuroserpin, a related mammalian serpin that inhibits thrombolytic proteases, or M-T7. Serp-1 and neuroserpin inhibited growth of the pancreatic cancer cell line Hs766t (P=0.03 and P=0.01, respectively) at 4 weeks after implantation. Serp-1 also inhibited growth of a second pancreatic cancer cell line MIA PaCa-2 in mice (P=0.02). Growth of the human breast cancer line MDA231 was not inhibited by Serp-1. M-T7, in contrast, did not alter growth of any of the cancer cell lines tested after implant into SCID mice. Serpin inhibition of pancreatic tumor growth was associated with a significant decrease in splenocyte MDSC counts by flow cytometry (P=0.009), without detected change in other splenocyte subpopulations. Serp-1 and NSP treatment also significantly reduced macrophage infiltration in tumors (P=0.001). In summary two anti-inflammatory serpins reduced inflammatory macrophage invasion and pancreatic tumor cell growth, suggesting potential therapeutic efficacy.

Nanotechnology in bioscience and therapeutics has advanced tremendously in this decade. Many nanoparticle formulations as well as passive and active targeted agents have been developed and proved effective preclinically in proof-of-concept models of different cancers.Many of these formulations use polymer nanoparticles, liposomes, bubkyballs, fullerenes, carbon nanotubes, dendrimers, isotope tags, and PEG compounds. In effect, nanoparticle formulations have become the norm in chemoprevention. In this paper we review nanoformulations of bioactive compounds that have been tested for their potential mechanistic antiproliferative activity in breast cancer. We also discuss the possibility of enhancing the activity of these compounds using different innovative bioconjugation methods.

Immune escape and acquisition of tolerance by tumor cells are essential to cancer growth and progression. Therefore, considerable attention has been paid to overcoming the immune resistance of tumors as a novel strategy for cancer therapy. This review focuses on the tryptophan-catabolizing and immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO), and its functional role in gynecologic cancers, such as endometrial cancer, ovarian cancer, cervical cancer, and vulvar cancer. IDO induces tolerance to the host immune surveillance through suppressing the proliferation of effector T-cells or natural killer cells and their killer functions within the tumor microenvironment. In gynecologic cancers, IDO is highly expressed in more than half of cases, and tumoral IDO expression is correlated with advanced surgical stage and impaired patient survival. In preclinical studies in mice, an IDO inhibitor 1-methyltryptophan suppresses tumor growth and peritoneal dissemination, and increases the efficacy of chemotherapeutic agents. In summary, IDO is a novel prognostic indicator for endometrial, ovarian, cervical, and vulvar cancers. IDO inhibition may be a promising strategy to restore host anti-tumor immunity and to enhance the anti-tumor potential of current chemotherapy, radiotherapy, and immunotherapy for gynecologic cancers.

Colorectal cancer (CRC) is the second leading cause of death from cancer in the developed countries. Although great efforts have been made to achieve an early diagnosis, a large number of cases will present metastases. The natural history of metastatic (m) CRC has dramatically evolved in the recent years thanks to the introduction of modern chemotherapy and molecular therapies. With these agents the response rate has increased to 50% and survival has been improved not only progression free survival (PFS), which has reached 12 months, but also overall survival (OS) which is longer than 2 years.   Despite this progress many questions remain to be answered, mainly those related to the sequential regimens, drug rotation, alternant or intermitent schedules, optimal duration of chemotherapy, the role of maintenance chemotherapy and the role of doublets or triplets.   The optimal duration of chemotherapy is very important because it has a direct influence on the patient quality of life, survival and costs. There are several studies addressing this topic and the alternatives we have, such as “stop and go”, intermittent strategies or maintenance of only several agents and these studies reinforce the frequent behaviour of the oncologists to stop the treatment when the patient has obtained the maximum response. But there are some methodological problems in the analyzed trials which have determined that not all the professionals agree with this proposal.   With this context it is essential to perform well designed clinical trials incorporating new drugs and addressing these questions. This article tries to review briefly all these controversial points.

Background: Carcinomas of the renal pelvis and ureter are rare diseases. Previous reports suggest that squamous cell histology is associated with inferior survival. We present one of the largest population based analysis to date of survival in patients with upper urinary tract malignancies and a systematic review of the subject.
 
Methods: We analyzed the Surveillance, Epidemiology and End Results database for cancer specific survival rates in patients with renal pelvis and ureteral malignancies who were diagnosed between 1973 and 2004 in the SEER catchment geographic areas. The primary exposure of interest was the underlying histology, squamous cell versus transitional cell differentiation. We performed descriptive statistics, non parametric survival analysis, and cox proportional hazard analysis.
 
Results: We identified 13,213 eligible patients, 7,716 renal pelvis and 5,497 ureteral carcinomas. Among this cohort, 179 patients had squamous cell carcinoma (SCC), 12,395 had transitional cell carcinoma (TCC), including 121 papillary, and 619 had other histologies. Overall, patients with SCC histology fared worse. The median overall survival time was 10 months for SCC and 63 months for TCC. The cox analysis revealed a HR 3.7 (95% CI 3.0-4.5) for SCC when compared to TCC and corrected for decade of diagnosis, age, gender, prior treatment, and race. The difference between the two groups was entirely attributable to survival differences in patients with loco-regional disease. However, when stratified by lymph node involvement this difference disappeared for patients with locally involved lymph nodes (p = 0.84) and for patients with clear lymph nodes (p = 0.92).
 
Conclusions: SCCs of the upper urinary tract present at a higher clinical stage and appear to represent more aggressive disease when compared to other histologies. However, when appropriately staged according to lymph node status, the survival of TCC and SCC of the upper urinary tract is identical when compared stage by stage.