Radiosensitization by intratumoral administration of cisplatin in a sustained-release drug delivery system.
OBJECTIVE
Effects of combining local irradiation and intratumoral (i.t.) administration of cisplatin (CDDP) in a sustained-release drug delivery system (epi gel) were studied in a murine SCCVII squamous cell carcinoma model in mice.


METHODS
The epinephrine injectable gel was used as a drug delivery system. Intratumoral pharmacokinetics of CDDP was studied by using 195mPt-CDDP. The tumor volume quadrupling time (TVQT) and tumor growth delay (TGD) time were used to evaluate the antitumor efficacy of treatment regimens.


RESULTS
The concentration and residence of 195mPt-CDDP was significantly higher in tumors treated with 195mpt-CDDP/epi gel than in tumors treated with 195mPt CDDP gel or 195mPt-CDDP suspension. Intratumoral administration of CDDP/epi gel (4 mg/kg) produced an average TGD time of 15.5 +/- 2.8 days, which was 5.2 - 7.4 times longer than CDDP suspension i.t. or i.p. When combined with a single dose of radiation (10 Gy), i.t. administration of CDDP/epi gel was 2.0 - 3.6-fold as effective as administered i.t. in suspension (39.2 +/- 4.1 vs. 19.8 +/- 3.9 days of TGD, P < 0.05) or i.p. in solution (39.2 +/- 4.1 vs. 11.0 +/- 1.6 days, P < 0.001) in inhibiting tumor growth and produced 20-60% complete remission of tumors. When combined with fractionated irradiation, pre-irradiation CDDP administration was more effective than post-radiation administration (26.7 vs. 12.1 days of TGD, P < 0.05). Mice treated with CDDP/epi gel i.t. alone or in combination with irradiation, had little systemic toxicity.


CONCLUSIONS
Intratumoral administration of CDDP using the sustained-release drug delivery system is an efficient and safe method to maximize the drug concentration in tumor, minimize the systemic toxicity and enhance antitumor efficacy of irradiation.
Ning
S
S
Department of Radiation Oncology, Stanford University Medical Center, CA 94305-5105, USA.
Yu
N
N
Brown
D M
DM
Kanekal
S
S
Knox
S J
SJ
D000818:Animals; D001345:Autoradiography; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019583:Dose Fractionation, Radiation; D016503:Drug Delivery Systems; D005500:Follow-Up Studies; D015552:Injections, Intralesional; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016896:Treatment Outcome
D003692:Delayed-Action Preparations; D011838:Radiation-Sensitizing Agents; D002945:Cisplatin