Volume 26, Issue 1

Ovarian cancer is the most frequent cause of gynecological cancer-related death. Unfortunately, many patients are diagnosed at an advanced stage and have a poor prognosis. The standard treatment for advanced disease involves maximal cytoreductive surgery and chemotherapy based on platinum compounds and taxanes. Patients presenting at an advanced stage have a higher risk of recurrence. The development of drug resistance currently represents a major obstacle in the systematic treatment and, therefore, the discovery of new anticancer agents and approaches should improve the poor prognosis of these patients. Folate receptor α is overexpressed in epithelial ovarian cancer (EOC), but has limited expression in nonmalignant human tissues. The degree of folate receptor expression corresponds with the stage and grade of the disease. Because of this, folate receptor α seems to be a potential therapeutic target for the treatment of ovarian cancer. Currently, several approaches have been studied to target this protein in ovarian cancer treatment. This review summarizes current knowledge about the potential usage of folate receptors as prognostic and predictive biomarkers as well as their role in the management and targeted therapy of ovarian cancer.

Pterins are heterocyclic molecules of biological importance that contain several basic sites. These molecules can be protonated in aqueous solution resulting in a wide variety of structures that differ in their site of protonation and tautomeric form. In the present study, density functional theory (DFT) calculations were used to determine the relative energies of various protonated tautomers of 6-methylpterin in aqueous solution. A total of 32 different structures are compared resulting from protonation at six different sites on six pterin tautomers. MP2 calculations were also used to support the calculated energies of the six most stable structures. We find that the most basic sites among all 6-methylpterin tautomers is N1, N8, and N5 of the lactam, respectively, followed by N1 of the lactim. Calculated charge densities of the neutral 6-methylpterin structures using a natural population analysis (NPA) support protonation at these sites.

Folic acid and pterin derivatives are important heterocyclic compounds found in a variety of biological systems and have been shown to be photochemically active. Understanding the amount of binding that various pterins have with biological macromolecules under physiological conditions is important in predicting what specific biomolecules will bind with pterins and may, therefore, result in photochemical damage from charge-transfer reactions. The relative binding of folic acid, or pteroyl-L-glutamic acid (PteGlu), 6-methylpterin (Mep), 6-hydroxymethylpterin (Hmp), 6-formylpterin (Fop), and 6-carboxypterin (Cap) with bovine serum albumin (BSA), electrically neutral lipid (ENL), polyguanylic acid (Poly G), polycytidylic acid (Poly C), polyadenylic acid (Poly A), polythymidylic acid (Poly T), Micrococcus luteus DNA (72% GC), Escherichia coli DNA (50% GC), calf thymus DNA (42% GC), and Clostridium perfrigens DNA (27% GC) in neutral phosphate buffer were studied. Our results indicate that PteGlu demonstrated strong binding to neutral lipids, while the other pterins showed minimal binding, and BSA had a significant binding to PteGlu, Cap, and especially Fop. Our results also reveal a high affinity for DNA by PteGlu, which suggests that a relatively high percentage of folic acid is bound to DNA before photochemistry occurs.

Formation of neopterin, a biomarker of the activated human immune system, is linked with tryptophan (TRP) and phenylalanine (PHE) metabolism. To obtain normal values, in this study, serum concentrations of neopterin as well as of TRP, PHE and their respective metabolites kynurenine (KYN) and tyrosine (TYR) were investigated in 100 successive blood donor serum specimens from the University Clinics of Innsbruck, Austria. In addition, nitrite concentrations were determined. Donors had passed anamnestic examination at entry and were therefore considered as healthy. The mean age of participants was 49±11.4 (mean±SD) years; 18% were older than 60 years. Both genders were included in the analysis. Neopterin concentrations measured by enzyme-linked immunosorbent assay were 5.9±1.6 nmol/L (mean±SD). Levels of amino acids and metabolites were determined by HPLC. Mean KYN and TRP concentrations were 1.78±0.42 μmol/L and 67.4±10.2 μmol/L, respectively. KYN to TRP ratio (KYN/TRP), an estimate for the activity of tryptophan-degrading enzyme indoleamine 2,3-dioxygenase, was 26.7±6.2 μmol/mmol. Mean PHE and TYR concentrations were 65.2±11.1 μmol/L and 90.6±22.9 μmol/L. PHE to TYR ratio (PHE/TYR), an estimate for the activity of PHE-converting enzyme phenylalanine hydroxylase, was 0.75±0.14 μmol/μmol. Nitrite concentrations, estimated by Griess-Ilosvay reagent, were 44.9±32.0 μmol/L. Males were taller and heavier than females (both p<0.01), but body mass index did not differ. Males presented with significantly higher TRP and TYR concentrations than females (both p<0.05). There existed significant correlations between neopterin and KYN (rs=0.368), KYN/TRP (rs=0.453), TYR (rs=–0.267; all p<0.01) and PHE/TYR (rs=0.236; p<0.05) concentrations. Data indicate that also in a population of healthy individuals an association exists between “low-grade” immune activation as is indicated by slightly higher neopterin concentrations and biochemical alterations in the amino acid metabolism. Although minor, such changes may interfere with psychoneuroimmunological regulatory networks and thus be of clinical relevance.

A rare phenotype-genotype correlation of atelencephalic aprosencephaly in a fetus with free trisomy 13 karyotype, obtained by pregnancy termination for holoprosencephaly during the 26th gestational week, is presented. Lack of cerebral hemispheres and presence of rudimentary diencephalon, brain stem and hypoplastic cerebellum were revealed. Agenesis of the eyeball, of the optic nerve and of the pyramids of the medulla oblongata was established. Skull and face examination found craniostenosis, microcephaly, cella turcica agenesis, cyclopia, cleft palate and nose agenesis.The correlation between the most common karyotype of trisomy 13 and the very rare brain abnormality atelencephalic aprosencephaly suggests that the study of parental karyotype is desirable to inform parents about its accidental and non-hereditary nature in a probable future pregnancy.