levoleucovorin and Pituitary-Neoplasms

Topics: Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma; Combined Modality Therapy; Cushing Syndrome; Female; Fluorouracil; Humans; Leucovorin; Pituitary Neoplasms

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 αT3-1, 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.

Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Caspase 7; Caspase 9; Cathepsin B; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cytochromes c; Dacarbazine; DNA Damage; Drug Synergism; Female; Folic Acid Antagonists; Histones; Leucovorin; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred NOD; Mice, SCID; Mitochondria; Neoplasm Invasiveness; Neoplasm Transplantation; Phosphorylation; Pituitary Neoplasms; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Pyrimethamine; Rats; Temozolomide; Up-Regulation; Xenograft Model Antitumor Assays

We report the case of a 64 year old male patient with a history of ischemic heart disease who underwent surgery for an abdominal mass. The histological diagnosis was highly malignant non-Hodgkin's lymphoma. After surgery the patient was admitted to our Department and received 6 courses of chemotherapy according to the COP schedule, followed by radiotherapy to the left upper abdominal region and ipsilateral lung base. The patient achieved partial remission. One month later he began to complain of left axillary lymphadenomegaly, polydipsia and polyuria. A NMR brain scan showed a hypophyseal mass. The patient was treated with DDAVP and chemotherapy with the PRO-MACE protocol; the polyuria and lymphadenomegaly disappeared and the size of the hypophyseal mass reduced markedly. The clinical picture was, therefore, attributed to a hypophyseal localization of the non-Hodgkin's lymphoma, which is a very rare manifestation of lymphomatous spread to the central nervous system. Our case is also interesting because it shows that a favorable outcome can be obtained with chemotherapy, provided that the latter is sufficiently aggressive. This is not necessarily the case with radiotherapy which may also be followed by late and severe neurologic sequelae.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Diabetes Insipidus; Doxorubicin; Etoposide; Humans; Leucovorin; Lymphoma, Non-Hodgkin; Magnetic Resonance Spectroscopy; Male; Methotrexate; Middle Aged; Pituitary Neoplasms; Prednisone; Procarbazine; Tomography, X-Ray Computed; Vincristine