Growth hormone releasing hormone plasmid supplementation, a potential treatment for cancer cachexia, does not increase tumor growth in nude mice

Abstract

Growth hormone releasing hormone (GHRH) is known to have multiple anabolic effects and immune-stimulatory effects. Previous studies suggest that treatment with anabolic hormones also has the potential to mitigate the deleterious effects of cancer cachexia in animals. We studied the effects of plasmid-mediated GHRH supplementation on tumor growth and the role of antitumor immune cells with two different human tumor cell lines, NCI-H358 human bronchioalveolar carcinoma and MDA-MB-468 human breast adenocarcinoma, subcutaneously implanted in nude mice. GHRH supplementation by delivery of human GHRH from a musclespecific GHRH expression plasmid did not increase tumor progression in tumor-bearing nude mice. Male animals implanted with the NCI-H358 tumor cell line and treated with the GHRH-expressing plasmid exhibited a 40% decrease in the size of the tumors (Po.02), a 48% increase in white blood cells (Po.025) and a 300% increase in monocyte count (Po.0001), as well as an increase in the frequency of activated CD3 Keywords: plasmid; GHRH; cachexia; electroporation; muscle T hree of the hormones largely responsible for postnatal growth in animals and humans include growth hormone releasing hormone (GHRH), which stimulates growth hormone (GH) production and secretion from the anterior pituitary, 1 and insulin-like growth factor-I (IGF-I) that is responsible for many of the indirect effects of GH.2 The effects of these hormones on development, growth, metabolism and regeneration have been widely documented.3,4 Recent studies in different animal models and humans have also shown that GHRH has immunestimulatory effects, both through stimulation of the GH axis and direct actions as an immune-modulator. 5Conflicting data exist regarding the role of the GHRH-GH-IGF-I axis in tumorigenesis and cancer-associated pathology. Some studies have suggested that carcinogenesis is dependent upon critical plasma levels of GH and IGF-I.6 GH-or IGF-I-deficient animals are resistant to chemically induced carcinogenesis.7 Circulating IGF-I levels play an important role in tumor development and metastasis 8 and IGF-II mRNA levels are increased in some tumor lines.9 By contrast, other studies have failed to demonstrate an effect of GH on cancer development 10 or have concluded that GH may actually improve the efficacy of cancer chemotherapy. 11Preclinical studies in rodents have suggested that anabolic hormones, such as GH and IGF-I, may reverse the catabolic state associated with cachexia, one of the major complications of cancer and cancer therapies, 12 as well as inhibit metastases in tumor-bearing animals. 13,14 In this study, the use of species-specific GHRH was not necessary. Numerous studies have shown that GHRH of different mammalian origin or GHRH analogs exert similar effects in species such as dogs, pigs, cattle and rodents. 15,16 In a previous study in immunocompetent mice with implanted LL-2 adenocarcinoma cell line, we showed that stimulation of the GH axis by intramuscular delivery of a GHRH plasmid increased serum IGF-I concen...

Effect of ghrelin and anamorelin (ONO-7643), a selective ghrelin receptor agonist, on tumor growth in a lung cancer mouse xenograft model

“…The finding in our study that ghrelin and anamorelin do not promote tumor growth, even in the presence of elevated GH and IGF-1, is consistent with findings from other studies evaluating GH-based therapies in tumor-bearing animals [9, 23–26], as well as in formal carcinogenicity studies in tumor-free animals [27], as summarized below.…”

“…Ghrelin activity is thought to be mediated by both growth hormone (GH)-dependent and GH-independent mechanisms [8]. However, the short half-life (∼30 min), and parenteral administration requirement of ghrelin has limited its clinical usefulness, and interest has switched to the development of orally available ghrelin mimetics [9–11]. One of these, anamorelin (ONO-7643, formally known as RC-1291), is a GRLN receptor agonist currently in development for the treatment of non-small-cell lung cancer (NSCLC)-related anorexia and cachexia.…”

Electroporation-Enhanced Nonviral Gene Transfer for the Prevention or Treatment of Immunological, Endocrine and Neoplastic Diseases

“…Also, in our laboratory we designed new plasmid backbones (pAV0201 series) and synthetically produce them. Using optimized backbone plasmids, we obtained long-term transgene expression at physiologic levels in various mammals, including cows and dogs [Khan, A.S. et al, 2005a;Tone, C.M. et al, 2004].…”

Combined treatment with GH, insulin, and indomethacin alleviates cancer cachexia in a mouse model

“…Similarly, GH has been reported to have no effect on the growth of human bronchoaveolar carcinoma and human breast adenocarcinoma (Khan et al 2005). GH increases anabolic activity, and some of its effects may also be mediated by increasing the immune response (Redelman et al 2008).…”

“…Importantly, a study of tumorbearing mice indicated that stimulation of the GH-insulinlike growth factor (IGF) axis did not promote tumor growth (Khan et al 2005). A clinical study of cancer patients indicated that administration of GH alone or in combination with INS led to bodyweight gain and increased upper arm muscle mass and strength (Berman et al 1999).…”