Tumor metastasis inhibition with the prostacyclin analogue cicaprost depends on discontinuous plasma peak levels

Abstract

Stable prostacyclin analogues exert a strong inhibitory effect on lymphogenous as well as haematogenous tumor metastasis in a series of tumor lines. The strong inhibition of metastasis was achieved by repeated once-daily i.g. applications. The mechanism of antimetastatic action is related to the expression of functional IP-receptors (PGI-receptors). As cellular assay systems indicated that the IP-receptor mediated signalling is down-regulated upon continuous exposure to prostacyclin or stable derivatives, it has been questioned whether a mode of drug application with constant plasma drug levels may potentially result in a decrease of the antimetastatic effect. We addressed this question using the stable prostacyclin analogue cicaprost in a disease model by comparing i.g. applications given once daily with a continuous administration of equivalent doses via drinking water. Very similar to our previous investigations in the 13762NF MTLn3 rat mammary carcinoma model, cicaprost administered by i.g. application strongly reduced lung and lymph node metastasis. In contrast, administration of equivalent doses via drinking water leading to lower but constant steady-state plasma levels failed to exert inhibitory effects. Plasma and urine levels of cicaprost were measured with a sensitive radioimmunoassay on the last treatment day. Pharmacokinetic evaluation demonstrated a similar bioavailability of cicaprost in both groups. This result first demonstrates a treatment failure of a prostacyclin derivative in a chronic disease model in association with a continuous drug administration leading to constant plasma levels. A desensitization of receptor signalling by constant plasma levels may be a possible mechanism for treatment failure.