The current state of pemetrexed in ovarian cancer

Abstract

A number of Phase I and II clinical trials have evaluated the use of pemetrexed in patients with ovarian cancer. Thus far, there are no randomized studies that address the role of pemetrexed compared to current, standard treatments. The activity of single agent pemetrexed in platinum-resistant patients is worth exploring. Biomarker-driven randomized, clinical trials and patient selection are key for the future development of pemetrexed.

Mass Spectrometric/Bioinformatic Identification of a Protein Subset That Characterizes the Cellular Activity of Anticancer Peptides

“…As shown in Figure , a distinct pattern can be seen in the profiles based on comparing the treatments using peptidic inhibitors (frame A) with the reference drug PMX (frame B) in the CSD-OC, A2780/CP, and IGROV-1 cell lines. Up-regulation of key proteins involved in purine and pyrimidine synthesis, such as TS and DHFR, is a common phenomenon associated with acquired resistance to substrate-like inhibitors. , Because the selected A2780 cell line model is known to be sensitive to antifolate drugs such as PMX, the mild response observed after the administration of this drug could be attributed to the development of resistance mechanisms in our derived cell lines. ,− …”

“…Human TS (hTS) is a known target for anticancer drugs. As a dimer, hTS catalyzes the conversion of 2′-deoxyuridine-5′-monophosphate (dUMP) to 2′-deoxythymidine-5′-monophosphate (dTMP) and requires N 5 ,N 10 methylenetetrahydrofolate (MTHF) as a cofactor. 5 Classical inhibitors of the protein used in clinical therapy are N 5 ,N 10 methylentetrhydrofolate analogs such as pemetrexed (PMX) and raltitrexed (Figure 1).…”

“…As a dimer, hTS catalyzes the conversion of 2′-deoxyuridine-5′-monophosphate (dUMP) to 2′-deoxythymidine-5′-monophosphate (dTMP) and requires N 5 ,N 10 methylenetetrahydrofolate (MTHF) as a cofactor. 5 Classical inhibitors of the protein used in clinical therapy are N 5 ,N 10 methylentetrhydrofolate analogs such as pemetrexed (PMX) and raltitrexed (Figure 1). Their protein binding site and mode of action have been thoroughly characterized by X-ray crystallography and enzyme kinetic studies (Figure 2C,D).…”

“…8 Consequently, OCs that are resistant to Pt drugs may also be less sensitive to anti-hTS drugs. 9,10 In an effort to overcome drug resistance induced by these drugs, we have recently identified a new class of peptidic compounds that inhibit hTS with a novel mechanism of action and reduce cancer cell growth. 11,12 Among these, the peptide with the best activity profile, LR (LSCQLYQR), inhibits the intracellular enzyme in cisplatin-sensitive and cisplatin-resistant OC cell lines without causing the typical protein overexpression associated with acquired resistance to PMX, thus showing the potential of this innovative hTS inhibition strategy.…”

“…OC first line treatment is based on platinum drugs (Pt drugs) that may cause the development of a Pt drug-resistant phenotype with increased concentrations of hTS and other related folate-dependent proteins, such as dihydrofolate reductase (DHFR); therefore, this treatment regimen may trigger the development of cross-resistance to anti-hTS drugs . Consequently, OCs that are resistant to Pt drugs may also be less sensitive to anti-hTS drugs. , …”