dihydropyridines and Neoplasm-Metastasis

Dexniguldipine (DNIG) is the R-enantiomer of the dihydropyridine derivate niguldipine. DNIG showed a binding affinity to the P-glycoprotein (P-gp) and therefore it is to be assumed to block the P-gp pumping mechanism. This open phase I study was conducted to determine the maximal tolerated dose (MTD) and safety of intravenously administered DNIG alone and in combination with vinblastine in patients with a metastatic or locally advanced cancer. Additionally, serum levels of DNIG were assessed and compared between dosage groups to investigate the intravenous dose linearity. The study was divided into two parts concerning DNIG administration. In part I the patients received DNIG for four hours daily over four consecutive days and additionally 0.15 mg/kg vinblastine at day 3. Treatment was started with 1 mg/kg/4h, and whenever the drug was well tolerated the dosage was increased. In part II the patients received up to three courses of a four-hour infusion (5 and 7 mg/kg/4h) of DNIG followed by a continuous infusion for 48 hours (5 and 7 mg/kg/24h). Twenty-six patients entered this trial and were given at least one infusion of DNIG; vinblastine was given immediately after the 4-hour infusion. One to seven courses and dosages from 1-11 mg/kg were administered. In five patients the dose limiting toxicity was seen in cardiovascular adverse events such as a drop in blood pressure, decreased heart rate and in one patient an AV block III. Most frequent adverse events were nausea, dizziness, vomiting, peripheral paresthesia, atactic gait, mild constipation, polyuria, hypocalcemia; all disappeared within 24 hours after discontinuation of infusion. A linear increase in DNIG serum concentration with increasing doses was found following intravenous infusion of DNIG over a four-hour period. Long-term infusion regimes over a period of two or five days resulted in reasonably constant DNIG serum levels. MTD was determined at 5 mg/kg/4h. It is to be assumed that the MTD for continuous infusion of DNIG is higher than 5 mg/kg/24h, but this was not followed up in the study and must be the aim of a later trial.

Topics: Adult; Aged; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Metastasis; Neoplasms; Vinblastine

Three calcium channel blockers of the dihydropyridine class were tested in vitro for their effects on tumor cell-platelet-endothelial cell interactions and in vivo for antimetastatic properties. Felodipine, nimodipine and nifedipine inhibited tumor cell-induced platelet aggregation in vitro in a dose-dependent manner. These compounds also inhibited platelet-enhanced tumor cell adhesion to endothelial cells in vitro. Lung colony formation ("experimental" metastasis) and spontaneous pulmonary metastasis were inhibited by felodipine, nimodipine and nifedipine. From the present studies on three calcium channel blockers of the dihydropyridine class we hypothesize that calcium channel blockers may represent a new generic class of antimetastatic agents.

Topics: Animals; Calcium; Calcium Channel Blockers; Cell Adhesion; Cell Communication; Cell Line; Dihydropyridines; Dose-Response Relationship, Drug; Endothelium; Female; Male; Mice; Neoplasm Metastasis; Platelet Aggregation; Pyridines; Rats