Phase I Trial on sms‐D70 Somatostatin Analogue in Advanced Prostate and Renal Cell Cancer

Abstract

Plasma concentrations and tolerability of a novel somatostatin analogue sms-D70 were studied in patients with metastatic hormone-resistant prostate cancer (HRPC) or metastatic renal cell cancer. To overcome the limitations of the octapeptides having affinity only to somatostatin receptor subtypes 2 and 5, HRPC expressing mainly somatostatin receptors 1 and 4, a somatostatin derivative based on the natural somatostatin having affinity to all five somatostatin receptor subtypes, was developed. The in vivo stability of this dextran-conjugated derivative, somatostatin-D70, was confirmed previously in animal studies, and the nanomolar "panaffinity" has been shown in in vitro receptor binding studies on cell lines transfected with the somatostatin receptor genes. Sms-D70 was given with subcutaneous injection once a week at dose levels of 5, 10, 20, 35, and 50 mg. For pharmacokinetic studies, sms-D70 was labeled with 131I. Fourteen patients were treated, of whom 10 had prostate and 4 renal cell cancer. The kinetic data revealed high stability with a long half-life in the blood. The drug was well tolerated, and no grade 4 (WHO) toxicity was observed. The maximal tolerated dose could not be established due to the lack of dose-limiting toxicities. Objective PSA responses were not recorded in these heavily treated patients, but subjective stabilization of pain was observed and urinary symptoms were alleviated in four patients. Three patients with metastatic HRPC received 5-10-mg intravenous injections of sms-D70 once weekly for 4-14 months on a compassionate use basis. In all cases, serum PSA values decreased more than 50% from the pretreatment level, but these results are difficult to interpret due to concomitant treatments given to these patients. In conclusion, sms-D70 was well tolerated in the treatment of metastatic prostate and renal cell cancer, but no responses were found in these heavily treated patients.

“Antisurvival” Factor Treatment for Hormone Refractory Prostate Cancer: Secondary Hormonal Ablation Using Somatostatin Analogs

“…Thus the somatostatin derivative SMS D70 already has a higher affinity to all 5 receptor subtypes compared to the previously used octapeptides. Although the tolerance has been tested in a phase I study with 10 patients, because of the study design, with an inhomogeneous patient group and a number of varying treatment modalities, it was not possible to obtain a clinically useful answer in this first study [55].…”

Nanocarriers for Nuclear Imaging and Radiotherapy of Cancer

“…Following conjugation with dextran to improve its in vivo kinetics [196], biodistribution 99m Tc or 125 I labeled dextran-somatostatin revealed good in vivo stability of the conjugate, increased plasma half and high affinity accumulation in tumors [196,206,207]. Phase I trials of 131 I labeled dextran-somatostatin conjugate injected subcutaneously once a week in patients with metastatic prostate or renal cancer showed long blood half-life and no cases of drug induced toxicity [208]. There was subjective stabilization of pain, relief of urinary symptoms and a 50% decrease in serum prostate specific antigen (PSA) values from the pretreatment level.…”

XAF1 expression and regulatory effects of somatostatin on XAF1 in prostate cancer cells

“…Somatostatin, originally identified as a neuropeptide inhibiting growth hormone release more than 30 years ago, is widely present in central and peripheral human cells/tissues including prostate. Somatostatin has been shown to exert a potent anti-tumour action by affecting tumour cell proliferation, apoptosis, angiogenesis and the host's immune response [17-21]. Octreotide is an analogue of somatostatin and has been used in clinical practice since data emerged in the 1980 s confirming its ability to palliate carcinoid syndrome [22].…”