Beyond peroxisome proliferator-activated receptor gamma signaling: the multi-facets of the antitumor effect of thiazolidinediones.

Certain members of the thiazolidinedione (TZD) family of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, such as troglitazone and ciglitazone, exhibit antitumor activities; however, the underlying mechanism remains inconclusive. Substantial evidence suggests that the antiproliferative effect of these TZD members in cancer cells is independent of PPARgamma activation. To discern the role of PPARgamma in the antitumor effects of TZDs, we have synthesized PPARgamma-inactive TZD analogs which, although devoid of PPARgamma activity, retain the ability to induce apoptosis with a potency equal to that of their parental TZDs in cancer cell lines with varying PPARgamma expression status. Mechanistic studies from this and other laboratories have further suggested that troglitazone and ciglitazone mediate antiproliferative effects through a complexity of PPARgamma-independent mechanisms. Evidence indicates that troglitazone and ciglitazone block BH3 domain-mediated interactions between the anti apoptotic Bcl-2 (B-cell leukemia/lymphoma 2) members Bcl-2/Bcl-xL and proapoptotic Bcl-2 members. Moreover, these TZDs facilitate the degradation of cyclin D1 and caspase-8-related FADD-like IL-l-converting enzyme (FLICE)-inhibitory protein through proteasome-mediated proteolysis, and down-regulate the gene expression of prostate-specific antigen gene expression by inhibiting androgen activation of the androgen response elements in the promoter region. More importantly, dissociation of the effects of TZDs on apoptosis from their original pharmacological activity (i.e. PPARgamma activation) provides a molecular basis for the exploitation of these compounds to develop different types of molecularly targeted anticancer agents. These TZD-derived novel therapeutic agents, alone or in combination with other anticancer drugs, have translational relevance in fostering effective strategies for cancer treatment.

Primary medical therapy of micro- and macroprolactinomas in men.

The presentation and long-term therapeutic responses of PRL-secreting pituitary tumors in men have been only partially studied. Gender-specific differences in tumor size at clinical presentation and possible differences in tumor biology in men compared to women make it important to determine treatment outcomes of male patients with prolactinomas. We performed a retrospective review of men with prolactinomas medically managed at Massachusetts General Hospital between 1980 and 1997. We identified 46 male patients with prolactinomas managed with medical therapy alone. Twelve patients had microadenomas, defined as a serum PRL level greater than 15 ng/mL and a normal pituitary scan or a tumor smaller than 1 cm. Thirty-four patients had macroprolactinomas, defined by a serum PRL greater than 200 ng/mL and pituitary adenoma larger than 1 cm. Bromocriptine, quinagolide, and/or cabergoline were administered as medical therapy. All patients had at least one follow-up visit, and the most recent serum PRL measurement after initiating dopamine agonist therapy was reported. Baseline clinical characteristics for patients with macroprolactinomas and microprolactinomas showed a larger proportion of patients with macroprolactinomas reporting a history of headache (74% vs. 0%), whereas the prevalence of sexual dysfunction and testosterone deficiency was similar between the two groups. Median serum PRL at presentation was 99 ng/mL (range, 16-385 ng/mL) vs. 1,415 ng/mL (range, 387-67,900 ng/mL), in the microprolactinoma and macroprolactinoma groups, respectively. A normal PRL level was achieved in a similar percentage of men with microprolactinomas vs. macroprolactinomas (83% vs. 79%, respectively). Although the majority of patients in both groups were treated with bromocriptine, a comparable number of patients with microprolactinomas vs. macroprolactinomas achieved a normal PRL level with cabergoline therapy. The response rates for bromocriptine and cabergoline were similar in both groups. No patient with a microprolactinoma required hormone replacement therapy, in contrast to patients with macroprolactinomas, who required thyroid, testosterone, and/or glucocorticoid replacement therapy. No patient had evidence of an increase in tumor size during therapy. In summary, we investigated the clinical presentation and treatment outcome in men with prolactinomas. We found that normalization of serum PRL levels occurs in approximately 80% of men with prolactinomas. Of importance, dopamine agonist administration yielded similar biochemical remission rates in men with microprolactinomas and macroprolactinomas.

Retrograde transport of nerve growth factor (NGF) in motoneurons of developing rats: assessment of potential neurotrophic effects.

The potential functional significance of nerve growth factor (NGF) receptors in spinal motoneurons was studied in newborn rats. 125I-NGF was specifically retrogradely transported by motoneurons from their peripheral nerve terminals. This transport was blocked by an excess of unlabeled NGF but not by cytochrome c. 125I-cytochrome c was not transported. The monoclonal anti-rat NGF receptor antibody, but not a control antibody, was also transported. Despite this ability of motoneurons to transport NGF, treatment of newborn rats with this factor did not increase motoneuron size or synthesis of neurotransmitter enzymes and did not prevent cell death after axotomy. We conclude that NGF receptors of spinal motoneurons can bind, internalize, and retrogradely transport NGF. However, these receptors do not mediate the classic trophic effects of NGF.