HYALURONIDASE PRETREATMENT PRODUCES SELECTIVE MELPHALAN ENRICHMENT INMALIGNANT-MELANOMA IMPLANTED IN NUDE-MICE

Preclinical and clinical observations suggest that the administration of hyaluronidase (Hyase) shortly before that of chemotherapy increases the access and, thus, the effectiveness of aniticancer drugs in tumor s. To examine this hypothesis as well as the selectivity of such a the rapeutic approach potentially beneficial in isolated limb perfusion, t he Hyase-induced distribution of melphalan was measured in tumor-beari ng nude mice with respect to the mode of drug administration using RP- 18 ion-pair high-performance liquid chromatography (HPLC) with fluorim etric detection. Melphalan alone (50 mu mol/kg) or a combination of me lphalan (50 mu mol/kg) and Hyase (100,000 IU/kg) was injected either i .p, or s.c. in the vicinity of the tumors. The s.c. melphalan injectio n caused a 4-fold rise in melphalan concentration (59 mu M) in the tum ors as compared with i.p. application (15 mu M). Only minor effects we re observed with respect to the route of melphalan application on its distribution in other tissues (ca. 13 mu M in plasma, 15 mu M in muscl e, 30 mu M in the liver, 26 mu M in the kidney, and 21 mu M in the tes ticle). Irrespective of the route of Hyase coadministration, the enzym e increased the concentration of i.p. injected melphalan in all tissue s to ca. 20 mu M in the tumor, 15 mu M in plasma, 27 mu M in muscle, 4 0 mu M in the liver, 29 mu M in the kidney, and 28 mu M in the testicl e. In contrast, s.c. injected melphalan was selectively accumulated by the tumors after both s.c, and i.p. Hyase administration (462 and 388 mu M, respectively). Melphalan enrichment in the tumors was higher (1 6- to 32-fold higher than in the other tissues) after i.p. administrat ion of Hyase since, in contrast to s.c. injection of the enzyme, its i .p. administration caused a decrease in the concentration of the cytos tatic in all other tissues as compared with the s.c. administration of melphalan alone.