The somatostatin analogue octreotide (SMS 201-995) exerts potent anti-proliferative effects in a number of experimental cancer models. Here we report on the inhibitory effect of octreotide in combination with the chemothera-peutic agents mitomycin C, doxorubicin, 5-fluorouracil, or taxol on the growth of AR42J pancreatic cancer cells in vitro. The dose-dependent anti-proliferative effects of mitomycin C, doxorubicin and taxol were synergistically enhanced by octreotide. Combinations of octreotide and 5-fluorouracil resulted either in additive or, at high concentrations of the chemotherapeutic agent, in synergistic interactions. Combined treatment with doxorubicin and octreotide was also studied for time dependency and potential efficacy in tumour-bearing animals. Pretreatment (24 h) with doxorubicin resulted in clear synergy. However, pretreatment with octreotide 24 h prior to addition of doxorubicin resulted only in an additive interaction. It was shown in AR42J-tumour-bearing nude mice that the combination of doxorubicin and octreotide was well tolerated. Tumour growth was inhibited to 9% of controls, compared with 44% in the doxorubicin alone arm (day 14 of treatment). Our in vitro and in vivo interaction studies suggest that octreotide potentiates the effect of various chemotherapeutic agents in a synergistic or additive manner.

The aim of the present study was to selectively target a β-emitter-labelled octreotide analogue to somatostatin (SRIF)-receptor-expressing tumours and to evaluate the feasibility of SRIF-receptor-mediated radiotherapy by delivering a lethal dose of radiation to the tumour. The most promising compound in a series of DTPA-coupled octreotide analogues was DTPA-benzyl-acetamido-D-Phe¹, Tyr³ctreotide (SDZ413). In vitro, SDZ413 binds with nanomolar affinity to SRIF-receptors (IC50 = 4.0 nM) and inhibits growth hormone release from primary cultures of rat pituitary cells with an IC₅₀ of 7.2 nM. Biodistribution studies with [⁹⁰Y]SDZ413 demonstrated a fast and significant SRIF-receptor-specific accumulation of the labelled conjugate (tumour/muscle ratio after 24 h: 52/1). [⁹⁰Y]SDZ413 was effective in the radiotherapy of SRIF-receptor-positive tumours in a nude mouse model. A single treatment with [⁹⁰Y]SDZ413 led to a significant decrease (25%) of tumour mass. This effect was mediated by the intact radioligand, since treatment with [⁹⁰Y]SDZ978, a derivative of SDZ413 which does not bind with high affinity to SRIF-receptors or with the unlabelled SDZ413 alone, failed to affect tumour growth. These results suggest that receptor-targeted radiotherapy with a ⁹⁰Y-labelled octreotide analogue represents a new strategy for the treatment of SRIF-receptor-positive tumours that have been previously diagnosed with OctreoScan®¹¹¹ (pentetreotide).

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Quantitative magnetic resonance imaging (MRI) has been used for the in vivo size determination of subcutaneously implanted Dunning R3327-H tumors in male Copenhagen-Fisher rats (N = 18). Images have been recorded using a multislice spin-echo sequence SE(1000/36) with a resolution of 0.2 x 0.2 mm2 in the imaging plane and a slice thickness of 2 mm. The reliability in the MRI size determination was of the order of 10%. The MRI results were compared with caliper measurements. Five months after tumor implantation nine rats were castrated. Orchiectomy led to a marked and statistically significant reduction in tumor growth rate as determined by both methods of quantification. Qualitative MRI information regarding the tumor morphology was compared with that for histological specimens.

The antiproliferative effect of somatostatin-14 and its analog octreotide on in vitro pancreatic and breast tumor cells has led to the suggestion that octreotide may have further oncological indications in addition to gastroenteropancreatic tumors. To extend these in vitro observations, we evaluated the effect of octreotide in rodent models of pancreatic and breast tumors. Octreotide of 5 or 50 μg b.i.d. in nude mice bearing solid MiaPaCa pancreatic tumors (subline 21) or ZR-75-1 breast tumors induced significant inhibition of tumor growth from week 2 until the end of treatment at week 5. After 5 weeks the mean volume of ZR-75-1 tumors in animals treated with the 50-μg regimen was 48% that of control. Autoradiographic studies showed a high percentage (71 %) of ZR-75-1 tumors to be somatostatin receptor-positive. In addition, the growth of ZR-75-1 cells in vitro was significantly inhibited by octreotide. The drug was also tested in a second breast cancer model, DMBA-induced mammary tumors in rats, and continuous administration of 10 μg/kg/h over 6 weeks led to an approximately 50% reduction in the number of tumors arising in the rat mammary gland. These data suggest that pancreatic and breast cancer may be among the malignant diseases clinically susceptible to octreotide.