IMPROVEMENT OF COMBINED-MODALITY THERAPY WITH CISPLATIN AND RADIATIONUSING INTRATUMORAL DRUG ADMINISTRATION IN MURINE TUMORS

The aim of these studies was to increase the therapeutic ratio by achi eving higher tumor concentrations of cisplatin during the course of a fractionated irradiation treatment. Specific goals were to test, first ly, whether multiple drug injections could be replaced by a single slo w release implant of cisplatin, and secondly, whether the therapeutic potential of the combined treatment could be increased by administerin g the drug intratumorally. Drug administration routes tested were intr aperitoneal (i.p.) of drug in solution, intratumoral (i.t.) of drug in solution, and intratumoral of drug in a slow release formulation. The latter consisted of a hydrogel polymer formulated into rods which wer e implanted into the center of subcutaneous tumors. For drug alone, bo th i.t. routes (solution or polymer) produced higher therapeutic gains than i.p. administration, as judged by tumor growth delay for a given weight loss. When combined with radiation, dose response curves were always shifted to lower doses and were steeper than for radiation or d rug alone, although isobologram analysis indicated additivity. In a fi rst series, drug enhancement ratios ranged from 1.6 to 2.6, and were h ighest for the i.t. groups. In a second series, X-ray enhancement rati os ranged from 1.1 to 1.7, with overlap between results from the diffe rent routes. Therapeutic ratios, however, were highest for the i.t. gr oups in both series. Slow release rods produced the highest therapeuti c gains in the first series, while i.t. administration of drug in solu tion was approximately as effective in the second series. It is conclu ded that i.t. administration of cisplatin in a slow release vehicle is a relatively simple and effective way of providing high tumor drug le vels during a fractionated radiation scheme which can lead to signific ant therapeutic improvements compared with administering the drug syst emically.