The effect of heparin on the cytotoxicity and uptake of anti-neoplastic drugs in cultured Burkitt lymphoma cells.

SUMMARY Preliminary clinical studies have been reported suggesting an increased response rate to a five-drug combination program in lung cancer patients who were anticoagulated with heparin. This study was undertaken to determine the effect of heparin on the cytotoxicity and cellular drug uptake of four antineoplastic agents. Burkitt lymphoma cells (P3J) in continuous culture were incubated with heparin in a concen tration of 0.5 unit/mi for 0 or 72 hr prior to the addition of radioisotopically labeled nitrogen mustard, methotrexate, 6-mercaptopurine, or 5-fluorouracil. Cytotoxicity and cellular drug uptake were then determined. Heparin alone had no effect on cell growth, viability, or DNA synthesis, as measured by thymidine-3H incorporation, during the log phase of culture growth over 72 hr. The cytotoxic effect of the four antitumor drugs also was not altered by incubating the cells with heparin for 0 or 72 hr. The uptake of the radioactively labeled agents in heparin-treated cultures was not significantly different from that of control cultures. preventing further fibrin deposition, allowing the physiological fibrinolytic system to remove the existing peritumor fibrin deposits. This could lead to increased tumor penetration of drugs or increased sensitivity to immune mechanisms. Both augmentation and inhibition of cellular transport of methotrexate by other antineoplastic drugs and antibiotics have been reported (3!). Enhanced antitumor response to alkylating agents complexed to heparin has also been noted with in vivo animal studies (7, 22). Since heparin can affect the surface properties of tumor cells (23, 24) and interfere with a number of enzyme systems (6), this study was undertaken to determine whether the reported enhancement of drug response could be due to a direct effect of heparin on the cellular uptake and cytotoxicity of various chemothera peutic agents. These studies were performed with Burkitt lymphoma cells grown in cell culture. Cultured Burkitt cells are useful as a model system. Since they are derived from a human neoplastic cell line, they grow to high density in culture media (2 X 106 cells/mi), and they are responsive to a number of chemotherapeutic agents. Genetic and cytological studies have verified that Burkitt cell lines grown in culture are derived from the malignant cells of the original neoplasm (12).