Drug resistance overcoming

Etoposide (XV) is a semisynthetic gylcoside derivative of podophyllotoxin, which is one of the most extensively used anticancer drugs in the treatment of various types of tumors [64,65]. The anticancer activity of this drug is mainly due to its ability to inhibit an ubiquitous and essential enzyme human DNA topo II [66,67]. Despite its extensive use in the treatment of cancers, it has several limitations, such as poor water solubility, drug resistance, metabolic inactivation, myelosuppression, and toxicity [68]. In order to overcome these... 

Hallaert DY, Jaspers A, van Noesel CJ et al (2008) c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL implications for therapeutic targeting of chemoresis-tant niches. Blood 112 5141-5149... 

Ryser, H.P., Shen, W.C. (1978). Conjugation of methotrexate to poly(L-lysine) increases drug transport and overcomes drug resistance in cultured cells. Proc. Natl. Acad. Sci. U.S.A., 75, 3867-3870. 

The combination of structural simplicity of epothilones with respect to paclitaxel, together with their very interesting activity profile appealed different research teams, interested to overcome limitations of taxanes (poor solubility, multi drug-resistance - MDR [61-63]). Investigations on epothilones were focused on the interaction between the ligands and the paclitaxel binding site (as well as the possible similar portions between epothilones and taxanes) in order to find common pharmacopores to be used in activity improvement and design of novel molecules. 

Vock CA, Ang WH, Scolaro C, Phillips AD, Lagopoulos L, Juillerat-Jeanneret L, Sava G, Scopelliti R, Dyson PJ (2007) Development of ruthenium antitumor drugs that overcome multidrug resistance mechanisms. J Med Chem 50 2166-2175... 

The proteasome is a large multisubunit proteolytic complex that participates in the degradation of proteins critical for cell cycle regulation. The proteasome inhibitors can overcome drug resistance. This effect is thought to be mediated through prevention of activation of NF-kB (nuclear transcription factor-icB) by proteasome inhibition. NF-kB is considered as one of the key factors involved in apoptotic pathways... 

The MDR transporter is of importance in drug resistance in antiprotozoal and anticancer chemotherapy and hence compounds that inhibit this transporter are potentially very useful as adjuncts to chemotherapy to overcome such drug resistance (Table 13.7). This chapter also deals with numerous plant-derived compounds that inhibit various other enzymes (Table 13.8). 

Sadava, D. Phillips, T. Lin, C. Kane, S. E. Transferrin overcomes drug resistance to artemisinin in human small-cell lung carainoma cells. Cancer Lett, 2002, 179(2) 151-156. 

The antibacterial effect of penicillin was discovered by Alexander Fleming in 1929. The extensive use of / -lactam antibiotics such as penicillin has saved thousands of lives but also created major resistance problems in hospitals and in the community worldwide, leading to increased morbidity, mortality, and healthcare costs. The conversion of penicillin into penam has been extensively investigated in order to overcome the drug resistance. Two approaches to selenopenams, selenium analogs of the penam, including a selenazole skeleton, have been reported. 

In particular, the system was able to overcome drug resistance and cross the blood-brain barrier. Preclinical studies on the DOX-loaded pluronic micelles SP1049C revealed superior tumor inhibition and extended lifespan to free drug. Phase I clinical studies showed a lower degree of DOX toxicity for SP1049C than for the free DOX, and three of 21 patients treated with SP1049C had transient partial responses. ... 

Mamot, C. Drummond, D.C. Hong, K. Kirpotin, D.B. Park, J.W. Liposome-based approaches to overcome anticancer drug resistance. Drug Resistance Updates 2003, 6, 271-279. 

Fig. 13.2 Imatinib wrapping modification engineered to overcome drug resistance in the C-Kit kinase. This resistance is promoted by the somatic mutation Asp816Val. The mutation induces the dehydron Phe811-Ala814 in the activation loop which in turn can be targeted or wrapped by suitably modifying imatinib at the position highlighted by the rectangle [3]...

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