Targeted Drug Strategies for Cancer and Inflammation by Larry H. Matherly, Ndeye Diop-Bove (auth.), Ann L. Jackman,

By Larry H. Matherly, Ndeye Diop-Bove (auth.), Ann L. Jackman, Christopher P. Leamon (eds.)

The discoveries highlighted during this ebook parallel the emergence of leading edge “molecular distinct” small molecules and monoclonal antibodies, i.e. brokers that focus on proteins inside of hugely activated sign transduction pathways that regulate proliferation. a number of the tumor-targeted options defined inside move the limits among what’s thought of to be “molecular unique” as opposed to traditional systemic remedy. notwithstanding, the most subject matter of this quantity is the folate receptor (FR), with a lot of the content material taken with its simple biology and rules in addition to its exploitation for precise remedy and diagnostic imaging.

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Example text

Thus, there is compelling rationale for seeking drugs that are selective for PCFT over RFC that could utilize this transporter effectively at the low pH within solid tumors with minimal transport into normal tissues mediated by RFC. 5 Impact of the loss of RFC function on antifolate activities. Comparison of the activities of pemetrexed (a), raltitrexed (b), and PT523 (c) in wild-type HeLa and RFC-null HeLa-R5 cells grown in complete RPMI 1640 medium containing 40 nM 5-formylTHF and exposed to different concentrations of drugs for 6 days, after which, cell numbers were quantified by the sulforhodamine B staining assay.

Pemetrexed is decreased. Low concentrations of folic acid can be used to block FRa-mediated transport with minimal effect on pemetrexed transport mediated by PCFT irrespective of pH. While thieno[2,3-d]pyrimidine antifolates have been identified that are selective for FRs over PCFT and RFC (Deng et al. 2009), pyrrolo[2,3-d]pyrimidine antifolate substrates without RFC activity were substrates for both FRs and PCFT (Deng et al. 2008a; Kugel Desmoulin et al. 2010; Wang et al. 2010) (see Matherly and Gangjee 2011).

Discrimination between PCFT and FRa based upon substrate selectivity is more challenging. FRa has a much higher affinity for folic acid than pemetrexed, while PCFT has a higher affinity for pemetrexed than folic acid. H. Matherly et al. pemetrexed is decreased. Low concentrations of folic acid can be used to block FRa-mediated transport with minimal effect on pemetrexed transport mediated by PCFT irrespective of pH. While thieno[2,3-d]pyrimidine antifolates have been identified that are selective for FRs over PCFT and RFC (Deng et al.

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