SummaryIn June 2005, an ad hoc Expert Committee formed by the Pituitary Society convened during the 9th International Pituitary Congress in San Diego, California. Members of this committee consisted of invited international experts in the field, and included endocrinologists and neurosurgeons with recognized expertise in the management of prolactinomas. Discussions were held that included all interested participants to the Congress and resulted in formulation of these guidelines, which represent the current recommendations on the diagnosis and management of prolactinomas based upon comprehensive analysis and synthesis of all available data.

Interleukin 12 (IL-12) seemed to represent the ideal candidate for tumor immunotherapy, due to its ability to activate both innate (NK cells) and adaptive (cytotoxic T lymphocytes) immunities. However, despite encouraging results in animal models, very modest antitumor effects of IL-12 in early clinical trials, often accompanied by unacceptable levels of adverse events, markedly dampened  hopes of the successful use of this cytokine in cancer patients. Recently, several clinical studies have been initiated in which IL-12 is applied as an adjuvant in cancer vaccines, in gene therapy including locoregional injections of IL-12 plasmid and in the form of tumor-targeting immunocytokines (IL-12 fused to monoclonal antibodies). The near future will show whether this renewed interest in the use of IL-12 in oncology will result in meaningful therapeutic effects in a select group of cancer patients.

Lovastatin (LOV), the drug recently introduced to treat hypercholesteremia, inhibits the synthesis of mevalonic acid. The effects ofLOV on the cell cycle progression of the human bladder carcinoma T24 cell line expressing activated p21 were investigated. At a concentration of 2-10 jpM, LOV arrested cells in GI and also prolonged-or arrested a minor fraction of cells in-the G2 phase of the cell cycle; at a concentration of 50 p&M, LOV was cytotoxic. The cytostatic effects were reversed by addition of exogenous mevalonate. Cells arrested in the cycle by LOV were viable for up to 72 hr and did not show any changes in RNA or protein content or chromatin condensation, which would be typical of either unbalanced growth or deep quiescence. The expression of the proliferation-associated nuclear proteins Ki-67 and p105 in these cells was reduced by up to 72% and 74%, respectively, compared with exponentially growing control cells. After removal ofLOV, the cells resumed progression through the cycle, they entered S phase asynchronously after a lag of~'6 hr.Because mevalonate is essential for the posttranslational modification (isoprenylatdon) of p2l', which in turn allows this protein to become attached to the cell membrane, the data suggest that the LOV-induced GI arrest may be a consequence of the loss of the signal trnsduction capacity of p21a. Indeed, while exposure of cells to LOV had no effect on the cellular content of p21 (detected immunocytochemically), it altered the intracellular location ofthis protein, causing its dissociation from the cell membrane and translocation toward the cytoplasm and nucleus. However, it is also possible that inhibition of isoprenylation of proteins other than p2l' (e.g., nuclear lamins) by LOV may be responsible for the observed suppression of growth of T24 cells.The drug lovastatin (LOV) was introduced to the clinic nearly 3 years ago to treat hypercholesteremia. It suppresses synthesis of mevalonic acid by blocking activity of 3-hydroxy-3-methylglutaryl-CoA reductase (EC 1.1.1.88). However, because mevalonic acid is also in the pathway of posttranslational modification of proteins that involve attachment of thioether-linked prenyl groups (isoprenylations) such as farnesylation (1), LOV, in addition to its anticholesterol activity, is also an inhibitor of these modifications.Recent evidence indicates that isoprenylation of the ras oncogene-encoded protein (p211a5) is an essential step enabling this protein to anchor to the cell membrane (2, 3).Because the signal transduction activity of p215, which is associated with its regulatory role in the cell cycle, requires its membrane attachment, suppression of the isoprenylation is expected to interfere with the cellular function of this protein. We have presently studied the effects of LOV on the cell cycle of the human bladder carcinoma T24 cell line. These cells express the activated form ofp21' resulting from a single point mutation of this oncogene (4,5). Since the cultures were maintained in the presence of fetal calf serum, ...

Photodynamic therapy is a promising antitumor treatment modality approved for the management of both early and advanced tumors. The mechanisms of its antitumor action include generation of singlet oxygen and reactive oxygen species that directly damage tumor cells and tumor vasculature. A number of mechanisms seem to be involved in the protective responses to PDT that include activation of transcription factors, heat shock proteins, antioxidant enzymes and antiapoptotic pathways. Elucidation of these mechanisms might result in the design of more effective combination strategies to improve the antitumor efficacy of PDT. Using DNA microarray analysis to identify stress-related genes induced by Photofrin-mediated PDT in colon adenocarcinoma C-26 cells, we observed a marked induction of heme oxygenase-1 (HO-1). Induction of HO-1 with hemin or stable transfection of C-26 with a plasmid vector encoding HO-1 increased resistance of tumor cells to PDT-mediated cytotoxicity. On the other hand, zinc (II) protoporphyrin IX, an HO-1 inhibitor, markedly augmented PDT-mediated cytotoxicity towards C-26 and human ovarian carcinoma MDAH2774 cells. Neither bilirubin, biliverdin nor carbon monoxide, direct products of HO-1 catalysed heme degradation, was responsible for cytoprotection. Importantly, desferrioxamine, a potent iron chelator significantly potentiated cytotoxic effects of PDT. Altogether our results indicate that HO-1 is involved in an important protective mechanism against PDT-mediated phototoxicity and administration of HO-1 inhibitors might be an effective way to potentiate antitumor effectiveness of PDT.

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