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Hyperthermia Enhances Tumor Uptake and Antitumor Efficacy of Thermostable Liposomal Daunorubicin in a Rat Solid Tumor

Laboratory for Radiobiology [C. v. B., J. J. K., J. B. A. K.] and Department of Internal Medicine, Division of Medical Oncology, [R. C. R., P. J. M. B.], Academic Medical Centre, University of Amsterdam, Meibergdreef 9. 1105 AZ Amsterdam, The Netherlands

The combination of local hyperthermia (HT) with thermostable liposomal daunorubicin (DaunoXome, DX) was investigated to assess targeted drug delivery to experimental tumors. Female Wag/Rij rats bearing solid R-1 rhabdomyosarcomas received i.v. injections of 10 or 15 mg/kg of DX or free-Daunorubicin (f-Dau). After a 1-h interval, HT (60 min at 43°C) was applied. Pharmacokinetics were studied in relation to tumor growth time (TGT), i.e., the time for tumors to reach twice their original volumes. Pharmacokinetic studies revealed that DX accumulation in tumor tissue was similar to f-Dau. A 5.4-fold increase (P = 0.0084) in tumor drug delivery was observed when DX was combined with HT, whereas liposomes remained stable. For f-Dau, HT had an additional effect on TGT at both drug doses tested (9.6 and 6.2 days, respectively, for 10 mg/kg, P = 0.0092; 17.7 and 13.7, respectively, for 15 mg/kg, P = 0.0431). For DX, HT significantly enhanced TGT of DX in the lower dose (17.1 and 6.4 days, respectively, P = 0.0005), whereas tumors did not regrow at day 25 after DX + HT in the higher dose. Unfortunately, after this time interval, the animals died of late toxicity, probably not related to HT. These results indicate that HT promotes extravasation of DX into tumor tissue and enhances its effectiveness. The finding that HT-induced drug release from the liposomes was not responsible for enhanced antitumor activity provides a rationale for further investigation of thermostable liposomes in conjunction with HT.

¹ To whom requests for reprints should be addressed.

Received 7/17/95. Accepted 11/28/95.

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