Search

This study was performed to determine the pharmacokinetics and local and systemic effects of cis-diamminedichloroplatinum II (cisplatin) released from an open-cell polylactic acid polymer when the drug delivery device was placed adjacent to a cortical allograft. Bilateral intercalary femoral allografts were implanted in six normal beagles. The polymer containing cisplatin was implanted adjacent to the allograft in one femur, and the polymer without cisplatin was implanted adjacent to the allograft in the contralateral femur. Systemic toxicity was evaluated clinically by hematologic and serum biochemistry tests and urinalysis. Healing of the allograft was monitored radiographically. The femora were evaluated biomechanically, histologically, and histomorphometrically 7.5 months after surgery. Total serum platinum levels were measured by atomic absorption spectrophotometry, and pharmacokinetic parameters were calculated. Healing was impaired slightly by the presence of the polymer with cisplatin, and systemic and local toxicity was mild and transient. After implantation of the polymer with cisplatin, the mean peak total serum platinum concentration was low (1.71 +/- 0.19 micrograms/ml). However, the area under the curve for total serum platinum concentration versus time for the first 21 days was large (27,050 +/- 3,201 micrograms.min/ml). When cisplatin was given as an intravenous bolus at a dose of 70 mg/m2 to six other beagles, the mean peak total platinum concentration was 8.80 +/- 2.1 micrograms/ml and the area under the curve was 940.3 +/- 256.7 micrograms.min/ml. These results indicate that a sustained release of cisplatin can be delivered safely from an open-cell polylactic acid polymer. This device may be useful in the treatment of solid tumors.

Five human small cell carcinoma of the lung (SCCL) cell lines selected from 25 established cultures were grown as three-dimensional spheroid tumor models in either spinner culture or in static, agar-coated multiwells. Volume doubling times for the cell lines were approximately 4.5 days. Decreases in spheroid volumes after exposure to a variety of chemotherapeutic agents were used as indicators of drug activity. To further quantify cell killing in SCCL spheroids by chemotherapeutic agents 24 hours after exposure to drugs, a technique was employed that measured maximum levels of incorporation of 125IUdR after continuous labeling for 48 hours. The results of the use of this assay report for SCCL spheroid responses to various concentrations of doxorubicin hydrochloride, cytosine arabinoside, mechlorethamine hydrochloride, cisplatin, or etoposide. Some evidence for an intertumor heterogeneous response to chemotherapy is presented for some of the drugs tested. This assay was also used to characterize a potentiated cell kill when etoposide is combined with cisplatin and to identify activity by a new compound, diazoacetylcholine iodide (DACI), which was synthesized as an agent targeted for SCCL cells.