Chemosensitizers

Bioluminescence in vitro chemosensitivity assays are now used to assess the sensitivity of tumor cells (obtained by surgical or needle biopsy) to different dmgs and combinations of dmgs. Cells are grown in microwell plates in the presence of the dmgs at various concentrations. If the tumor cells are sensitive to the dmg then they do not grow, hence total extracted cellular ATP, measured using the bioluminescence firefly luciferase reaction, is low. This method has been used to optimize therapy for different soHd tumors and for leukemias (306). 

Taniguchi M., Wang D. and Halpem M. (2000). Chemosensitive conductance and inositol 1,4,5-trisphosphate-induced conductance in snake vomeronasal receptor neurons. Chem Senses 25, 67-76. 

J. P., Galullo, V., Armistead, D. M., Saunders, J. O., Boger, J., Harding, M. W., Cellular and biochemical characterization of VX-710 as a chemosensitizer reversal of P-glycoprotein-mediated multidrug resistance in vitro, Anticancer Drugs 1997, 8, 125-140. 

High-dose chemotherapy with autologous HSCT is the therapy of choice for younger patients with chemosensitive relapse. 

Chen, S.Z., Jiang, M. and Zhen, Y.S. (2005) HERG K+ channel expression-related chemosensitivity in cancer cells and its modulation by erythromycin. Cancer Chemotherapy and Pharmacology, 56, 212-220. 

Carmichael J, DeGraff WG, Gazdar AF et al. (1987) Evaluation of a tetrazolium-based semiauto-mated colorimetric assay assessment of chemosensitivity testing. Cancer Res. 47 936-942. 

SMase activity (Mansat et al 1997) and downstream (by blocking the apoptotic effect of ceramide). However, the cross-talk between ceramides and DAG opens new intriguing avenues of research and may lead to better pharmacological maiupulation of key steps in the apoptosis/survival signaling cascade resulting in an increased chemosensitivity of neoplastic cells. 

Cyclopamine also interferes with cholesterol metabolism that results in decreased cholesterol synthesis and the accumulation of late biosynthetic intermediates. Cyclopamine was evaluated as an inhibitor of multi-drug resistance in tumor cells. Intrinsic or acquired resistance of tumor cells to cytotoxic drugs is a major cause of failure of chemotherapy. Both cyclopamine and the spirosolane alkaloid tomatidine from tomatoes act as potent and elfective chemosensitizers in multidrug-resistant cells (Lavie et ah, 2001). Therefore, plant steroidal alkaloids, such as cyclopamine and tomatidine, or their analogs, may serve as chemosensitizers in combination with chemotherapy and conventional cytotoxic drugs for treating multidrug-resistant cancers. 

Hon J, Wang D, Zhang R, Wang H. (2008) Experimental therapy of hepatoma with artemisinin and its derivatives In vitro an in vivo activity, chemosensitization, and mechanisms of action. Clin Cancer Res 14 5519-5530. 

Zhou J, Ong CN, Hur GM, Shen HM. (2010) Inhibition of the JAK-STAT3 pathway by andrographolide enhances chemosensitivity of cancer cells to doxorubicin. Biochem Pharmacol 79 1242-1250. 

Beltran PJ, Fan D, Fidler IJ, O Brian CA (1997) Chemosensitization of cancer cells by the staurosporine derivative CGP 41251 in association with decreased P-glycoprotein phosphorylation. Biochem Pharmacol 53 245-247... 

Chakrabarty S, Huang S (1996) Modulation of chemosensitivity in human colon carcinoma cells by downregulating protein kinase C alpha expression. J Exp Ther Oncol 1 218-221... 

Whitehurst AW, Bodemann BO, Cardenas J et al (2007) Synthetic lethal screen identification of chemosensitizer loci in cancer cells. Nature 446 815-819... 

For non-suspension cultures, suitable matrices include liquid overlay on agarose (59), Matrigel , or Cultrex (48, 92). More recently, micropatterned arrays have been developed for adherent 3-D spheroid cultures (56) and have been used to show reduced chemosensitivity of colorectal carcinoma cells to irinotecan (58). In some cases, 3-D cultures can be enhanced by the addition of host cells. This increases complexity, but inevitably decreases flexibility and speed of analysis. However, important insights into the role of host cells have emerged stromal cells modify the gene expression and response of many tumor cell types to chemotherapeutic agents (93) and tumor-associated myofibroblasts can enhance tumor invasiveness (94). 

Microarrays for the scalable production of metabolicaUy relevant tumour spheroids a tool for modulating chemosensitivity traits. Lab Chip 11 419-428... 

Pegram MD, Lipton A, Hayes DF, et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-pl 85HER2/neu monoclonal antibody plus cisplatin in patients with HER2/ neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 1998 16 2659-2671. 

Osaki S, Nakanishi Y, Takayama K, Pei XH, Ueno H, Hara N. Alteration of drug chemosensitivity caused by the adenovirus-mediated transfer of the wild-type p53 gene in human lung cancer cells. Cancer Gene Ther 2000 7 300-307. 

Condensation of l-[4,6-bis(allylamino)-l,33-triazin-2-yl]-4-piperidone (32) with amines 30 and 31 afforded the verapamil-like analogs 33 and 34 which were synthesized as potential drugs able to revert multidrug resistance (MDR). Both compounds show chemosensitizing activity but maintain some cardiovascular action <99JMC1687>. 

Squamous cell bronchogenic carcinoma G ng) Moderately chemosensitive Surgery and radiotherapy chemotherapy... 

A key question that cannot be answered using cell culture assays is whether dietary GAs can have similar effects. Importantly, evidence that dietary tomatine is effective against cancer was shown in a feeding study using rainbow trout, in which reduced tumor incidence was found in tomatine-fed trout (Friedman et al., 2007). Tomatidine has potential as a chemosensitizing... 

The MTT assay was initially developed as a quantitative assay for cell survival and proliferation, not as an in vitro assay for chemosensitivity testing. Further study was required to ascertain if the method accurately predicted the in vivo antitumor activities of anticancer agents. Shimoyama et al. [189] studied the predictability of the MTT assay with respect to a clonogenic assay (Sect. 4.1.1.3.) and showed excellent reproducibility and a close correlation to the in vivo predictability rate of the clonogenic assay. Another study [190] also showed that the MTT assay closely approximated (90%) the clinical activity of anticancer agents. Many authors have since utilized the MTT assay to determine the efficacy of polymeric anticancer drug conjugates. 

Key Words Bioinformatics chemosensitivity tumor cell cytotoxicity NC160 gene expression compoimd screen... 

Recently, Isshi et al. demonstrated that high levels of orotate phosphorybosyl transferase (OPRT) may be associated with increased sensitivity to 5-FU based chemotherapy (79). OPRT catalyzes the reduction of FUDP to the actively TS-inhibiting metabolite FdUMP, indicating a role for chemosensitivity to 5-FU. A recent study by Ichikawa et al. indicated that a newly identified SNP of OPRT exon 3 (G-to-A substitution) may be critical to predict toxicity to 5-FU based chemotherapy (80). 

Isshi K, Sakuyama T, Gen T et al. Predicting 5-FU sensitivity using human colorectal cancer specimens comparison of tumor dihydropyrimidine dehydrogenase and orotate phosphoribosyl transferase activities with in vitro chemosensitivity to 5-FU. Int J Clin Oncol 2002 7 335-342. 

Sohn KJ, Croxford R, Yates Z et al. Effect of the methylenetetrahydrofolate reductase C677T polymorphism on chemosensitivity of colon and breast cancer cells to 5-fluorouracil and methotrexate. J... 

Tassone P, Tagliaferri P, Perricelli A et al. BRCAl expression modulates chemosensitivity of BRCA 1-defective HCC1937 human breast cancer cells. BrJCawcer 2003 88 1285-1291. 

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