Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-2 (IL-2) is an immunostimulatory cytokine that induces activation of peripheral blood lymphocytes (PBL) which can mediate augmented tumor cytotoxicity. Several regimens using IL-2 as treatment for metastatic melanoma and renal carcinoma have shown measurable tumor responses in 10-20% of human patients. Our overall goals are to determine the efficacy of IL-2 as an adjuvant treatment for canine tumors. In order to evaluate the possibility to extend the use of IL-2 in vivo in the dog, we examined the ability of a clinically relevant (low) dose of human recombinant IL-2 (100 units/ml) to enhance the tumoricidal properties of canine PBL in vitro. This was particularly important considering the need to establish the effects on canine PBL by IL-2 at a dose that is potentially achievable in vivo with acceptable side effects. Our data show, for the first time, the ability to separate canine natural killer (NK) cell activity from lymphokine-activated killer (LAK) cell activity (induced with a low IL-2 dose) mediated by canine PBL against two canine cell lines (CTAC and CML-10) used as targets in 4 vs. 16 hour killing assays. LAK cells generated by stimulation of canine PBL with 100 units/ml of IL-2 for 72 hours, could kill CTAC or CML-10 targets up to 11 or 18 times more efficiently, respectively, than fresh PBL in a 4 hour assay. However, the killing of efficiency of the LAK cells was only 2- to 3-fold greater than that of the fresh PBL in a 16 hour assay. This apparent reduction in the killing efficiency of the LAK cells was mostly due to increased spontaneous NK activity by the fresh PBL after 16 hours in culture; both the LAK cells and the fresh PBL (NK cells) mediated a greater overall cytotoxicity after 16 hours than they did in the 4 hour assays. These results indicate that a low dose of human recombinant IL-2 can augment tumor killing by canine PBL in vitro, and suggest that it may be feasible to examine the potential use of IL-2 as an immunotherapeutic agent in tumor-bearing dogs.
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PMID:Induction of lymphokine-activated killer (LAK) activity in canine lymphocytes with low dose human recombinant interleukin-2 in vitro. 782 Jan 85

The proliferative cancer cell paradigm that has driven cancer drug development for the past 50 years has failed to generate treatments that cure most metastatic adult cancers. This view is supported not only by cumulative experience with conventional cytotoxic anticancer drugs, but also by the application of highly-targeted anticancer compounds against, for example, BCR-ABL in CML and mutant BRAF in metastatic melanoma. Such drugs often send their respective cancers into complete molecular remission but fail to effect cures because a small population of quiescent or slowly selfrenewing cancer cells that are drug and radiation resistant survive treatment indefinitely. This review explores the grounds for an emerging cancer paradigm that views cancer as a disorganized tissue with hierarchical cellular compartments in which the boudaries are less well-defined than in normal tissues with plasticity controlled by epigenetic changes mediated by the local microenvironment. Increased metabolic flexibility and adaptability give cancer cells an additional survival advantage that may be able to be targeted with drugs like metformin. Combining approaches that target the increased metabolic flexibility of cancer cells as well as ablating rapidly-proliferating cells and self-renewing cancer stem cells in individual cancers are needed to address the holy grail of cancer cure.
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PMID:Cell hierarchy, metabolic flexibility and systems approaches to cancer treatment. 2220 93

The oncologist dream is to provide more benefit with lower toxicity. The increasing knowledge of molecular mechanism for survival and proliferation of cancer cells leads to the development of targeted therapies with impressive results for some cancers even if not associated with chemotherapy. These targeted treatments could be monoclonal antibodies or tyrosine kinase inhibitors. Inactivation of only one oncogene can lead to the regression of tumours as well as the inhibition of only one pathway with one or more inhibitors. This result is related to the oncogenic addiction of these tumours. Examples are imatinib in CML and GIST, trastuzumab in HER2 positive breast cancer, gefitinib in mutated EGFR, crizotinib in EML4-ALK positive lung cancer and, also, vemurafenib in BRAF 600E mutated metastatic melanoma. We shall specifically discuss HER2 positive breast cancer, which represent some 15-20% of breast cancers and the recent targeted and bi-targeted therapies. Trastuzumab, an anti-HER2 monoclonal antibody has changed the prognosis of the disease improving survival in the metastatic and adjuvant setting. Lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER2 is approved with capecitabine in trastuzumab resistant patients and in combination with letrozole in first line. Unfortunately, 20% of patients receiving adjuvant trastuzumab relapse and metastatic patients only transienly respond to trastuzumab or lapatinib combined with chemotherapy. New HER2 targeted drugs are currently in development like pertuzumab, T-DMI or mTOR and PI3K inhibitors. New strategies combining these drugs with or without chemotherapy showed interesting results in metastatic and neoadjuvant trials. The selection of patients who will most benefit from these combinations is still a challenge. Currently, chemotherapy in association with anti-HER2 therapy remains the most effective treatment option.
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PMID:[Will targeted therapies replace chemotherapy?]. 2269 Apr 83