Human growth hormone gene transfer into tumor cells may improve cancer chemotherapy

Abstract

Chemotherapy remains the main tool for the treatment of cancers, but is often hampered by tumor cell resistance. In this context, the transfer of genes able to accentuate the effect of anticancer drugs may constitute a useful approach, as exemplified by inactivation of nuclear factor ( NF ) -B via direct transfer of a gene encoding a negative dominant of its natural inhibitor IB, leading to improved response to cancer chemotherapy. Following our previous report that transfection of human growth hormone ( hGH ) gene into human monocytic cell lines may also inactivate NF -B in another situation, we decided to test the consequences of hGH gene transfer on cancer treatments. We demonstrated that hGH -transfected human myeloid leukemia U937 cells were sensitized to an apoptotic signal mediated by the anticancer drugs. In parallel, we found that, by inhibiting degradation of IB, hGH gene transfer diminished NF -B entry into the nuclei of U937 cells exposed to daunorubicin. Finally, we report that hGH -transfected tumor cells engrafted in nude mice responded in vivo to chemotherapy with nontoxic doses of daunorubicin whereas, under the same conditions, control tumor cells remained insensitive. Overall, this study therefore suggests that hGH gene transfer may offer new therapeutic prospects in cancer therapy.

Potentiation of tumour apoptosis by human growth hormone via glutathione production and decreased NF-κB activity

“…The effect of hGH is mediated via a glutathione-dependent decrease in NF-kB translocation normally observed in response to TNF-a. We alsoconfirmed these findings in vivo, as injections of exogenous recombinant hGH in U937 tumour-engrafted nude mice led to increased tumour cell death together with decreased translocation of NF-kB in cell nuclei, in response to subtoxic doses of daunorubicin, an anthracycline agent activating NF-kB in our cells (Cherbonnier et al, 2002).…”

“…Moreover, daunorubicin, widely used in clinical practice, is able to induce apoptosis and activate NF-kB in our cells (Cherbonnier et al, 2002). We therefore decided to study the effect of exogenous recombinant hGH on chemotherapy delivered to nude mice engrafted with parental unmodified U937 tumours.…”

“…Another group of mice was then engrafted with fragments from these tumours (4 mm 3 ), pooled and randomly assigned to four groups of 10 mice: animals injected with saline solution; animals injected with 1.5 mg kg À1 of daunorubicin (dosage determined as previously reported (Cherbonnier et al, 2002); animals injected with 5 mg kg À1 of recombinant exogenous hGH (rhGH) based on the study of the in vivo effects of rhGH in a murine model of sepsis induced by Escherichia coli (Inoue et al, 1995); and animals injected with 1.5 mg kg À1 of daunorubicin and 5 mg kg À1 of rhGH. Daunorubicin was administered as a single intraperitoneal injection on three consecutive days.…”

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

“…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. 11 Preclinical 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.…”

Use of physiological doses of human growth hormone in haematological patients receiving intensive chemotherapy promotes haematopoietic recovery: a double-blind randomized, placebo-controlled study

“…Recent studies have shown an effect of hGH on cell survival by regulating nuclear factor-kappa B activity, leading to apoptosis in leukaemia cell lines. 9 Also, Cherbonnier et al 9,27 showed that hGH-transfected tumour cells engrafted in nude mice responded in vivo to chemotherapy with non-toxic doses of daunorubicin, whereas, under the same conditions, control tumour cells remained insensitive. We show that it is safe to use hGH in this group of patients treated intensively with chemotherapy and/or stem cell transplantation, and that it does not increase relapse rate and improves platelet reconstitution.…”