No abstract

Invasive pituitary adenomas (PAs) are generally refractory to conventional therapy and salvage treatment with temozolomide (TMZ). In addition to antiprotozoan effects, pyrimethamine (PYR) has recently shown its strong antitumor activity as an antineoplastic agent or in combination with TMZ in metastatic melanoma cells. In this study, the effects of TMZ, PYR or TMZ/PYR combination on rat/mouse PA cell lines aT3-1, GH3, MMQ and ATt-20 as well as GH3 xenograft tumor model were evaluated. TMZ/PYR combination synergistically inhibited proliferation, invasion and induced apoptosis of these PA cell lines in vitro. Strikingly, combination treatment with TMZ and PYR produced synergistic antitumor activity and enhanced the survival rate of GH3 xenograft tumor models without increasing systemic side effects. In addition, TMZ/PYR induced cell cycle arrest, increased DNA damage, upregulated the expression of cathepsin B, BAX, cleaved PARP and phosphorylated histone H2AX as well as elevated caspase3/7, 8 and 9 activities. The decreased expression of Bcl-2, MMP-2 and MMP-9 alone with cytochrome c release from mitochondria into the cytosol was also observed in the TMZ/PYR combination group. The increase in cell apoptosis due to combination with PYR was rescued by leucovorin. These data suggest that PYR may enhance the efficacy of TMZ via triggering both cathepsin B-dependent and caspase-dependent apoptotic pathways. Therefore, combination of PYR and TMZ may provide a novel regimen for invasive PAs refractory to standard therapy and TMZ.Pituitary adenomas (PAs) are the second most common intracranial neoplasms, accounting for approximately 15% of primary intracranial tumors. 1 Although most PAs are benign and grow expansively, approximately 35% are locally invasive and aggressive pituitary tumors with massive invasion of bone, dura and/or adjacent structures, and undergo rapid growth. 2 A subset of nonmetastatic invasive pituitary tumors displaying more aggressive behavior are called atypical PAs, and are characterized by fast invasive growth, increased mitotic activity, a Ki-67 labeling index greater than 3% and positive P53 immunoreactivity. 3 Although repeated surgeries, radiosurgery and alternative medical therapies are routinely used for invasive PAs and atypical PAs, they are generally refractory to these therapies and experience tumor recurrence. 4,5 Therefore, it is difficult to manage these invasive PAs owing to their size, invasiveness, accelerated growth and limited therapeutic options.Different chemotherapeutic agents have been tested for refractory PAs to inhibit tumor growth and improve prognosis. Recent case reports have documented that temozolomide (TMZ) has antitumor activity against these tumors. However, only 60% of the published cases responded to TMZ therapy, and exhibited a reduction in tumor mass, normalization of hormone levels and/or prevention of tumor regrowth. 6 A large number of invasive PAs failed to respond to TMZ and

Objective: The aryl hydrocarbon receptor interacting protein gene (AIP) is associated with pituitary adenoma (PA). AIP has not been sequenced in East Asian PA populations, so we performed this study in a Han Chinese cohort. Design: Our study included six familial PA pedigrees comprising 16 patients and 27 unaffected relatives, as well as 216 sporadic PA (SPA) patients and 100 unrelated healthy controls. Methods: AIP sequencing was carried out on genomic DNA isolated from blood samples. Multiplex ligation-dependent probe amplification and microsatellite marker analyses on DNA from the paired tumor tissues were performed for loss of heterozygosity analysis. Results: We identified three common and four rare single nucleotide polymorphisms (SNPs), one intron insertion, one novel synonymous variant, four novel missense variants, and a reported nonsense mutation in three familial isolated PA (FIPA) cases from the same family. Large genetic deletions were not observed in the germline but were seen in the sporadic tumor DNA from three missense variant carriers. The prevalence of AIP pathogenic variants in PA patients here was low (3.88%), but was higher in somatotropinoma patients (9.30%), especially in young adults (%30 years) and pediatric (R18 years) paients (17.24% and 25.00% respectively). All AIP variant patients suffered from macroadenomas. However, the AIP mutation rate in FIPA families was low in this cohort (16.67%, 1/6 families). Conclusion: AIP gene mutation may not be frequent in FIPA or SPA from the Han Chinese population. AIP sequencing and long-term follow-up investigations should be performed for young patients with large PAs and their families with PA predisposition.