Page 94 - Clinical Small Animal Internal Medicine

62 Section 2 Endocrine Disease

Selegilene (L‐deprenyl) inhibitor, attenuated POMC expression, inhibited corti­
VetBooks.ir serves to raise concentrations of dopamine in the brain, cotroph tumor cell proliferation, and induced apoptosis.
The monoamine oxidase B inhibitor L‐deprenyl, which
As predominantly nuclear EGFR expression was observed
has been used to treat hyperadrenocorticism in dogs.
tially targeted EGFR to mouse corticotroph cell nuclei,
The medication appears effective in some patients (20– in canine and human corticotroph tumors, we preferen­
30%) with pars intermedia disease with few side‐effects. which resulted in higher POMC expression and ACTH
Today, the medication is generally used in PDH patients secretion, both of which were inhibited by gefitinib.In
where the cost of monitoring ACTH stimulation tests athymic nude mice, EGFR overexpression enhanced the
and electrolytes would prohibit treatment with adrenal growth of explanted ACTH‐secreting tumors and further
enzyme blockers or adrenolytics. elevated serum corticosterone levels. Gefitinib treatment
decreased both tumor size and corticosterone levels; it
Retinoic Acid also reversed signs of hypercortisolemia, including ele­
Retinoic acid is an agent that has been shown to inhibit vated glucose levels and excess omental fat. These results
proliferation, invasion, and tumor growth in vivo and indicate that inhibiting EGFR signaling may be a novel
induces differentiation and apoptosis in different cell strategy for treating Cushing disease and studies in dogs
types. Some of these effects are mediated by a reduction and humans are under way.
in binding of the transcription factors AP‐1 and Nur77
to their cognate DNA sites; these factors are also essen­ Pituitary Surgery
tial in the control of the POMC gene, which gives rise to Several groups have described successful use of transs­
the precursor to ACTH and alpha‐MSH. Recently, it was phenoidal hypophysectomy (TSH) as a method of treat­
shown that retinoic acid inhibits ACTH secretion both ing PDH in dogs. Recently, we described a technique
in vitro and in vivo through an action on POMC gene for transsphenoidal removal of pituitary adenomas in
transcription and also inhibits corticotrophinoma devel­ 26 dogs with PDH using a high‐definition video tele­
opment and proliferation. scope. Pituitary tumors were removed using a modifi­
A randomized study comparing treatment with 2 mg/ cation of a transoral transsphenoidal approach. Surgery
kg/day of 9‐cis retinoic acid (n = 22) vs 20 mg/kg/day of was observed using a high‐definition video telescope
ketoconazole (n = 20) in dogs with Cushing disease was (VITOMTM) and localization of the sella was per­
recently performed. Clinical signs, plasma ACTH and formed by drilling pilot holes in the basisphenoid bone
alpha‐MSH, UCCR, and pituitary MRI were assessed followed by CT. There were no postoperative cerebro­
and compared at different time points for six months. A spinal fluid leaks, wound dehiscence, or surgical site
significant reduction in plasma ACTH, alpha‐MSH, and infections. Overall postoperative mortality was 19%,
UCCR was seen in the dogs treated with retinoic acid. with no mortality observed in the last 16 dogs, indicat­
Pituitary adenoma size was also significantly reduced at ing an initial learning curve. Follow‐up times ranged
the end of treatment. Survival time and all the clinical from three to 36 months. Sustained tumor control and
signs evaluated showed an improvement in the retinoic hormonal remission based on normalized ACTH and
acid‐treated dogs. No adverse events or signs of hepato­ UCCR measurements were observed in 20/21 (95%) of
toxicity were observed, suggesting that the drug is not dogs at one‐year follow‐up.
only effective but also safe. Retinoic acid treatment con­ Surgical experience and tumor size are likely impor­
trols ACTH and cortisol oversecretion as well as tumor tant variables in dogs undergoing TSH. The survival
size in dogs with ACTH‐secreting tumors, leading to rates at one, two, three, and four years in the study by
resolution of the clinical signs. This study highlights the Hanson et al. evaluating 181 patients were 86%, 83%,
possibility of using retinoic acid as a novel therapy in the 80%, and 79%, respectively. Disease‐free intervals (DFI)
treatment of ACTH‐secreting tumors in humans with were 90%, 77%, 72%, and 68%, respectively.
Cushing disease. In our study, one‐year survival was 81% (all five deaths
occurring within the first five days) with 100% of the sur­
EGFR Receptor Antagonists viving dogs in remission at three months and 95% (20/21)
We recently demonstrated that in surgically resected in remission at one year. To date, seven dogs have sur­
human and canine corticotroph cultured tumors, block­ vived >2 years and one dog >3 years.
ing EGFR suppressed expression of POMC, the ACTH Another important variable is tumor size. All the dogs
precursor. In mouse corticotroph EGFR transfectants, in our study had tumors with P/B ratios >0.32 and a
ACTH secretion was enhanced and EGF increased median P/B ratio of 0.73. Both the tumor size and extent
POMC promoter activity, an effect that was dependent of removal were typical for this series. Median tumor
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on mitogen‐activated protein kinase (MAPK). Blocking volume was 820 mm , which is nine times larger than the
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EGFR activity with gefitinib, an EGFR tyrosine kinase median volume of 89 mm reported by Hanson et al. In