Effects of Plasmid-Mediated Growth Hormone-Releasing Hormone in Severely Debilitated Dogs with Cancer

Abstract

Cachexia is a common manifestation of late stage malignancy and is characterized by anemia, anorexia, muscle wasting, loss of adipose tissue, and fatigue. Although cachexia is disabling and can diminish the life expectancy of cancer patients, there are still no effective therapies for this condition. We have examined the feasibility of using a myogenic plasmid to express growth hormone-releasing hormone (GHRH) in severely debilitated companion dogs with naturally occurring tumors. At a median of 16 days after intramuscular delivery of the plasmid, serum concentrations of insulin-like growth factor I (IGF-I), a measure of GHRH activity, were increased in 12 of 16 dogs (P < 0.01). These increases ranged from 21 to 120% (median, 49%) of the pretreatment values and were generally sustained or higher on the final evaluation. Anemia resolved posttreatment, as indicated by significant increases in mean red blood cell count, hematocrit, and hemoglobin concentrations, and there was also a significant rise in the percentage of circulating lymphocytes. Treated dogs maintained their weights over the 56-day study and did not show any adverse effects from the GHRH gene transfer. We conclude that intramuscular injection of a GHRH-expressing plasmid is both safe and capable of stimulating the release of growth hormone and IGF-I in large animals. The observed anabolic responses to a single dose of this therapy might be beneficial in patients with cancer-associated anemia and cachexia.

Intramuscular IL-12 Electrogene Therapy for Treatment of Spontaneous Canine Tumors

“…With the advances in the field of gene therapy, this new therapeutic tool is steadily gaining its acceptance also in clinical veterinary medicine. In the last decade, a number of gene therapy clinical trials have been conducted on companion animals, employing both viral and nonviral vectors and evaluating its effects primarily in oncologic, haematologic, musculoskeletal and cardiovascular diseases (Bergmann et al, 2003;Bodles-Brakhop et al, 2008;Dow et al, 2005;Draghia-Akli et al 2002;Herzog et al, 2001;Huttinger et al, 2008;Jahnke et al, 2007;Kamstock et al, 2006;Kornegay et al, 2010;Ohshima et al, 2009;Pavlin et al, 2011;Siddiqui et al, 2007;Sleeper et al, 2010;Z. Wang et al, 2007).…”

“…In the last few years, the number of reports on successful intramuscular EGT in dogs is steadily increasing. Therapeutic genes, delivered into canine skeletal muscle with this technique are genes encoding growth hormone releasing hormone (GHRH) (BodlesBrakhop et al, 2008;Brown et al, 2009;Draghia-Akli et al, 2002), human coagulation factor IX (hF.IX) (Fewell et al, 2001) and interleukin-12 (IL-12) (Pavlin et al, 2008). These studies showed a considerable clinical effect of intramuscular EGT in canine patients.…”

Long-term effects of plasmid-mediated growth hormone releasing hormone in dogs

“…Quality of life questionnaires were completed throughout the study, and 10 animals (n ¼ 1 from the cancer group and n ¼ 9 from the geriatric group) monitored for 444740 days post-treatment. While in our initial evaluation on cancer-afflicted dogs, 12 we included 19 controls, only two animals survived or were made available by owners for monitoring for more than 180 days after the baseline evaluation. These could not be included in the study for statistical reasons.…”

“…Most of the animals (75%) showed a physiological increase in serum IGF-I concentration. 12 Animals monitored longterm had IGF-I levels that peaked at 180 days, and diminished thereafter to 365 post-treatment, but were 10% above baseline. Long-term evaluation of the quality of life parameters, including exercise tolerance and activity level scores, also showed significant improvements.…”

“…13,14 Short-term responses to this plasmid in cancer-afflicted dogs has been described previously. 12 …”