endothelin-1 and Fibrosarcoma

This paper describes a model of tumor-induced bone destruction and hyperalgesia produced by implantation of fibrosarcoma cells into the mouse calcaneus bone. Histological examination indicates that tumor cells adhere to the bone edge as early as post-implantation day (PID) 3, but osteolysis does not begin until PID 6, correlating with the development of hyperalgesia. C3H/He mice exhibit a reproducible hyperalgesia to mechanical and cold stimuli between PID 6 and 16. These behaviors are present but significantly reduced with subcutaneous implantation that does not involve bone. Systemic administration of morphine (ED(50) 9.0 mg/kg) dose-dependently attenuated the mechanical hyperalgesia. In contrast, bone destruction and hypersensitivity were not evident in mice implanted with melanoma tumors or a paraffin mass of similar size. A novel microperfusion technique was used to identify elevated levels of the putative algogen endothelin (ET) in perfusates collected from the tumor sites of hyperalgesic mice between PID 7 and 12. Increased ET was evident in microperfusates from fibrosarcoma tumor-implanted mice but not from melanoma tumor-implanted mice, which are not hyperalgesic. Intraplantar injection of ET-1 in naive and, to a greater extent, fibrosarcoma tumor-bearing mice produced spontaneous pain behaviors, suggesting that ET-1 activates primary afferent fibers. Intraplantar but not systemic injection of the ET-A receptor antagonist BQ-123 partially blocked tumor-associated mechanical hyperalgesia, indicating that ET-1 contributes to tumor-induced nociception. This model provides a unique approach for quantifying the behavioral, biochemical, and electrophysiological consequences of tumor-nerve interactions.

Topics: Animals; Behavior, Animal; Calcaneus; Crosses, Genetic; Disease Models, Animal; Endothelin-1; Fibrosarcoma; Hindlimb; Hyperalgesia; Melanoma, Experimental; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Neoplasm Transplantation; Neoplasms, Experimental; Pain; Pain Measurement; Peripheral Nerves; Physical Stimulation; Tumor Cells, Cultured

Modification of blood flow by endothelin-1 (ET-1) was examined in the s.c. HSN fibrosarcoma and compared to normal tissues of anaesthetised CBH/CBi rats. The ET receptor subtypes involved in the response were investigated using the ET(A) and ET(B) receptor antagonists BQ-610 and BQ-788, respectively. Blood flow and vascular resistance were determined using the uptake of radiolabelled iodo-antipyrine (125I-IAP). BQ-610 or BQ-788 was infused for 30 min prior to blood flow determination. ET-1 was administered 15 min into the infusion time. BQ-610 and BQ-788 infused alone did not modify any vascular parameters. Tumour blood flow increased slightly following ET-1, contrasting with most normal tissues, in which blood flow was reduced. Vascular resistance increased in all tissues, including the tumour. Neither antagonist significantly modified the ET-1-induced changes in tumour blood flow or vascular resistance, whereas in the majority of normal tissues BQ-610 attenuated and BQ-788 potentiated the vascular resonse to ET-1. Our results show that the HSN tumour vasculature is only weakly responsive to ET- 1 and antagonism of its effects by BQ-610 and BQ-788. This contrasts with the majority of normal tissues, in which ET- 1 induces an intense vasoconstriction.

Topics: Animals; Blood Flow Velocity; Blood Pressure; Endothelin Receptor Antagonists; Endothelin-1; Female; Fibrosarcoma; Heart Rate; Hemodynamics; Neoplasms, Experimental; Oligopeptides; Piperidines; Rats; Receptor, Endothelin A; Receptor, Endothelin B; Vascular Resistance

Modification of tissue blood flow and tissue vascular resistance was examined in the female CBH rat, bearing a HSN fibrosarcoma, following bolus intravenous administration of 1 nM kg-1 endothelin-1 (ET-1) or 1 nM kg-1 sarafotoxin S6c (SX6c), selective agonists for endothelin A (ETA) and B (ETB) receptors respectively. Blood flow was measured 15 min after drug administration by the tissue uptake of 125I-labelled-iodoantipyrine. ET-1 and SX6c produced increases in mean arterial blood pressure (MABP) of 52 mmHg and 42 mmHg respectively. Blood flow to the tumour was unaffected by ET-1 treatment, whereas blood flow to normal tissues was reduced, the exception being the heart and the brain in which flow was increased. In contrast, tumour blood flow following SX6c was significantly increased, whereas blood flow in normal tissues was either unaltered or reduced. Vascular resistance was increased in all tissues and the tumour by ET-1 demonstrating that the tumour vasculature was constricting via ETA receptor activation. SX6c however, did not modify tumour vascular resistance, whereas it increased vascular resistance in all normal tissues, suggesting that the tumour lacks a functional population of ETB receptors. This discrepancy may provide a means for selectively modifying tumour blood flow.

Topics: Animals; Blood Pressure; Endothelin-1; Female; Fibrosarcoma; Rats; Regional Blood Flow; Vascular Resistance; Viper Venoms