DCA For NSC lung cencer

שלום, מה ידוע על ה- DCA האם זה טיפול משלים או במקום קונבנציונלי, והאם ניתן לטפל ב-DCA בארץ.כל אינפורמציה תועיל.

1: Br J Cancer. 2008 Oct 7;99(7):989-942 Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer קטעים ממאמר סקירה על DCA המתייחסים לקליניקה. The preclinical work on DCA (showing effectiveness in a variety of tumours AND relatively low toxicity) (Bonnet et al, 2007), its structure (a very small molecule), the low price (it is a generic drug) AND the fact that DCA has already been used in humans for more than 30 years, provide a strong rationale for rapid clinical translation. Here, we expand the scientific rationale AND discuss several practical points that will be important in the clinical evaluation of DCA as anticancer therapy. רעילות --------- A large number of children AND adults have been exposed to DCA over the past 40 years, including healthy volunteers AND subjects with diverse disease states. Since its first description in 1969 (Stacpoole, 1969), DCA has been studied to alleviate the symptoms OR the haemodynamic consequences of the lactic acidosis complicating severe malaria, sepsis, congestive heart failure, burns, cirrhosis, liver transplantation AND congenital mitochondrial diseases. Single-arm AND randomised trials of DCA used doses ranging from 12.5 to 100 mg kg-1 day-1 orally OR intravenously (reviewed in (Stacpoole et al, 2003)). Although DCA was universally effective in lowering lactate levels, it did not alter the course of the primary disease (for example sepsis). More than 40 nonrandomised trials of DCA in small cohorts of patients have been reported, but the first two randomised control trials of chronic oral therapy with DCA in congenital mitochondrial diseases were reported in 2006. In the first, a blinded placebo-controlled study was performed with oral DCA administered at 25 mg kg-1 day-1 in 30 patients with MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis AND stroke-like episodes) (Kaufmann et al, 2006). Most patients enrolled in the DCA arm developed symptomatic peripheral neuropathy, compared with 4 out of 15 in the placebo arm, leading to the termination of the study. Seventeen out of 19 patients had at least partial resolution of peripheral neurological symptoms by 9 months after discontinuation of DCA. This neurotoxicity resembled the pattern of length-dependent, axonal, sensorimotor polyneuropathy without demyelination. No other toxicities were reported. It is important to note that peripheral neuropathy often complicates MELAS because of primary OR secondary effects on peripheral nerves; for example these patients also have diabetes AND diabetes-related peripheral neuropathy. In contrast, another randomised placebo-controlled double-blinded study failed to show any significant toxicity of DCA, including peripheral neuropathy. In this study only one of 21 children with congenital lactic acidosis treated with DCA orally at 25 mg kg-1 day-1 for 6 months demonstrated mild peripheral neuropathy. Serial nerve conduction studies failed to demonstrate any difference in incidence of neuropathy in the 2 arms (placebo vs DCA). Sleepiness AND lethargy, muscular rigidity of the upper extremity AND hand tremor were reported in one patient in each group (Stacpoole et al, 2006). The higher incidence of peripheral neuropathy in adult MELAS patients may represent an intrinsic predisposition to this complication in MELAS OR its associated conditions, that is, diabetes mellitus; this toxicity might also be age-dependent. In summary, peripheral neuropathy is a potential side effect of DCA that appears to be largely reversible. As peripheral neuropathy is a frequent complication of taxane, platinum AND vinca-alkaloid chemotherapies, the risk for DCA-associated peripheral neuropathy may depend on whether cancer patients have prior OR concurrent neurotoxic therapy. יעילות נגד סרטן ----------------- There is substantial evidence in preclinical in vitro AND in vivo models that DCA might be beneficial in human cancer (Bonnet et al, 2007; Cairns et al, 2007; Cao et al, 2008; Wong et al, 2008). The concept is strengthened by the fact that LDH inhibition in mice with human cancer xenotransplants, also induced apoptosis AND inhibited growth, improving survival (Fantin et al, 2006). There is also 40 years of human experience with mechanistic studies of DCA in human tissues after oral use, pharmacokinetic AND toxicity data from randomised studies for 6 months AND 5-year use case reports. This supports an easy translation to early-phase clinical trials. Dichloroacetate could be tested in a variety of cancer types. The realisation that (i) a diverse group of signalling pathways AND oncogenes result in resistance to apoptosis AND a glycolytic phenotype, (ii) the majority of carcinomas have hyperpolarised/remodeled mitochondria, AND (iii) most solid tumours have increased glucose uptake on PET imaging, suggest that DCA might be effective in a large number of diverse tumours. However, direct preclinical evidence of anticancer effects of DCA has been published only with non-small cell lung cancer, glioblastoma AND breast, endometrial AND prostate cancer. In addition, the lack of mitochondrial hyperpolarisation in certain types of cancer, including oat cell lung cancer, lymphomas, neuroblastomas AND sarcomas (Chen, 1988), suggest that DCA might not be effective in such cases. Cancers with limited OR no meaningful therapeutic options like recurrent glioblastoma OR advanced lung cancer should be on top of the list of cancers to be studied. No patient with cancer has received DCA within a clinical trial. _______________________________________________________________ It is unknown whether previously studied dose ranges will achieve cytotoxic intra-tumoral concentrations of DCA. In addition, the overall nutritional AND metabolic profile of patients with advanced cancer differs from those in the published DCA studies. Furthermore, pre-exposure to neurotoxic chemotherapy may predispose to DCA neurotoxicity. Carefully performed phase I dose escalation AND phase II trials with serial tissue biopsies are required to define the maximally tolerated, AND biologically active dose. Clinical trials with DCA will need to carefully monitor neurotoxicity AND establish clear dose-reduction strategies to manage toxicities. Furthermore, the pharmacokinetics in the cancer population will need to be defined.