Effectiveness of Antitumor Agents Administered Subcutaneously to L1210 Leukemic Mice in Silicone Rubber Devices

Abstract

The therapeutic effects of a number of antineoplastic agents administered subcutaneously to L1210 leukemic mice in silicone polymer (Silastic®, Dow Corning Medical Grade) implants is reported. 1-β-d-arabinofuranosylcytosine (ara-C, cytarabine), two 5′-acylates of ara-C (the 1-adamantanecarboxylate [AdO-ara-C] and acetate [AcO-ara-C]) and two nitrosoureas [l-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea {CCNU} and 1-(2-chloroethyl)-3-trans-4-methylcyclohexyl)-1-nitrosourea {MeCCNU}], when administered in this manner, significantly increased survival time and, in the case of ara-C, CCNU, and MeCCNU, resulted in a considerable number of cures. Silastic cylinders containing ara-C (625 mg ara-C/kg) implanted up to 3 days prior to tumor inoculation yielded significant therapeutic effects, suggesting that ara-C was being released at a slow rate such that cytotoxic levels of ara-C persisted in the mice for several days. This ‘depot’ effect was confirmed by studies of ara-C plasma levels and excretion after administration of ¹⁴C-ara-C in this manner. Silastic cylinders containing CCNU (25 mg CCNU/kg), when implanted 4 h prior to tumor inoculation showed activity, but no therapeutic effect was observed when administration was 24 h prior to inoculation. Studies in which drug implants were removed at various times after implantation indicated that the necessary exposure time (for optimum therapeutic effect) is considerably longer for an S-phase (DNA synthetic) specific agent such as ara-C than for nonphase-specific agents such as CCNU.

Sustained release of carmustine (BCNU) for treatment of experimental intraocular malignancy.

“…Ocular examinations were repeated on alternate days during the follow-up period of 30 to 60 days. The effectiveness of treatment was evaluated by (1) comparing the extent of tumour growth in the anterior chamber; (2) noting the occurrence of local complications after local sustained release of carmustine and noting the distortion and perforation of the eye caused by tumour extension; (3) observing the animals for systemic toxic reaction as indicated by general activity, appetite, body weight, and white blood cell count; and (4) comparing the histopathological changes of the tumours. Test eyes were enucleated at 30 days or when they perforated if this occurred before 30 days.…”