ABSTRACT
At the time of diagnosis, more than one quarter of patients with medullary thyroid carcinoma (MTC) has distant metastases. Only few of these patients can be cured by surgery. Standard chemotherapy is characterized by low response rates and short response time. The establishment of eight human MTC cell lines provides a new basis for in vitro investigation of cytotoxic drugs. Camptothecin (CPT) and paclitaxel, which never have been investigated in the treatment of MTC, were tested for their cytotoxic profile in comparison with the clinically ineffective dacarbazine. Eight MTC cell lines were established from seven patients with MTC. IC(50) values were calculated from dose-response relationships using cell counts and a formazan dye assay (WST-1). IC(50) values were 3.5 +/- 1.2 nmol/liter for CPT and 8.2 +/- 1.9 nmol/liter for paclitaxel. Dacarbazine showed no reduction of cell proliferation at concentrations 10-fold higher than clinically achievable. Given peak plasma concentrations of 65 +/- 20 nmol/liter for CPT and 1 micro mol/liter for paclitaxel, these promising in vitro results provide a basis for the performance of clinical trials in patients with advanced MTC.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Camptothecin/pharmacology , Carcinoma, Medullary/physiopathology , Paclitaxel/pharmacology , Thyroid Neoplasms/physiopathology , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/pharmacology , Antineoplastic Agents, Phytogenic/administration & dosage , Camptothecin/administration & dosage , Cell Line, Tumor , Cell Survival/drug effects , Dacarbazine/administration & dosage , Dacarbazine/pharmacology , Dose-Response Relationship, Drug , Humans , Paclitaxel/administration & dosageABSTRACT
The affinity of MCF7 breast cancer cells to hyaluronan (HA) was investigated in an in vitro model. The cells form a tightly adhering monolayer on native HA with a concentration of 5 mg/ml. On native HA at higher concentrations the cells reduce their adhesion to the substrate in favor of increased intercellular bonds, resulting in a cluster-like aggregate that tends to detach from the substrate. Aggregate formation is accomplished after 12 h incubation. The phenomenon is independent of the CD44 receptor. Degradation of native HA by hyaluronidase abolishes aggregate formation even at high HA concentrations in favor of formation of a firmly adhering monolayer. This model may help to understand tumor spread on HA tissue structures and may explain therapy successes with hyaluronidase in tumor patients.
