The antitumour effect of the somatostatin analogue TT-232 depends on the treatment regimen
Introduction
Somatostatin, the naturally occurring peptide hormone has received attention ever since its first description in 1973 [1], [2], [3]. It has been shown to act as an inhibitory factor at different target sites of the endocrine system and reduce portal pressure, as well as to exhibit marked tumour inhibition either in vitro or in vivo. This peptide hormone antagonises several endocrine functions and effectively inhibits the enzyme tyrosine kinase, which is involved in the regulation of cell proliferation [4], [5], [6], [7]. In view of its widespread systemic action, the clinical use of somatostatin was evidently strongly dependent on a new analogue highly selective in either hormonal or antitumour action [8], [9]. In the past decade, a series of potent somatostatin analogues with antitumour activity in certain hormone dependent tumours were developed. We also developed several novel somatostatin analogues. One of them is TT-232, which contains a five residue ring (d-Phe-Cys-Tyr-d-Trp-Lys-Cys-Thr-NH2), and shows unique conformational characteristics compared to the other somatostatin analogues. The peptide was found to exert strong antitumour activity both in vitro and in vivo without interfering with growth hormone (GH) release. The mechanistic studies of the TT-232 had been already described in our publications [10], [11], [12], [13]. Our previous in vivo studies on transplantable S-180 sarcoma rodent tumour proved the significant antitumour effect of TT-232 [14]. In the case of S-180 sarcoma, the continuous infusion using implanted Alzet type osmotic minipump proved to be a much more effective route of treatment on both subcutaneous (s.c.) and intravenous (i.v.) administration than the intermittent injections applied twice a day for 2 weeks [15]. The antiproliferative activity of TT-232 correlated strongly with inhibition of tyrosine kinase in vitro, results programmed cell death (apoptosis) in a time and dose dependent manner [16]. TT-232 had no toxicity in a wide dose range (up to 120 mg/kg). The goal of our experiments was to study the therapeutic efficacy of TT-232 on the basis of survival and tumour growth inhibition using various aggressive rodent tumour models and applying different administration routes (s.c. and i.v. injection and infusion) and treatment schedules.
Section snippets
Compound
TT-232 was dissolved in buffer solution (pH 4.1) containing 0.1 M acetic acid, 0.1 M sodium acetate and 3% mannitol. The stock solution proved to be stable at 37 °C over 3 weeks.
Animals
Female inbred BDF1 and BALB/c mice from a specified pathogen free (SPF) breeding of the Department of Experimental Pharmacology, National Institute of Oncology (Budapest, Hungary), weighing 22–24 g were used for these experiments. The animals were fed with a sterilised standard diet (Biofarm) and had free access to tap
Treatments started on day 1 after tumour transplantation
Fig. 1A shows the significant inhibitory effect of TT-232 in the S-180 sarcoma tumour model. When TT-232 was given at a dose of 15 μg/kg, by i.p. or s.c. injection, twice a day for 2 weeks the tumour growth-inhibitory effect was 31 and 32%, respectively. Eighteen days after tumour transplantation the TT-232 administered via the s.c. minipump for 7 days evoked a significant (77%) tumour growth-inhibitory effect and a retardation of tumour development over 7 days. An 80% growth-inhibitory effect
Discussion
It has been well demonstrated both in vitro and in vivo that peptide hormones at a relatively low dose have to be present continuously in the vicinity of the target cells in order to exert a long-term action. This is very reasonable since they exert their action via second messengers [20], [21] that has to be maintained at a certain level for biological efficacy, while internalisation degradation or desensitisation mechanisms protect the cells from a strong pulse like effect from the hormone.
Acknowledgements
We thank Mrs. Anikó Besztercei and Mrs. Andrea Szobi for their excellent technical assistance. This work was supported by grants from the Hungarian Scientific Research Fund (OTKA, Nos. T-026087 and 17722), the Hungarian Ministry of Education (MKM FPFK-0215) and from the Hungarian Ministry of Health (ÉTT-01-1037).
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