Effectiveness of water soluble poly(L-glutamic acid)camptothecin conjugateagainst resistant human lung cancer xenografted in nude mice

A camptothecin (CPT) formulation that can be easily administered, is less t oxic, and has greater antitumor effect is needed. In this study, a water-so luble CPT derivative was obtained by direct coupling of CPT to poly(L-gluta mic acid) (PG) through the C20(S)-hydroxyl group. CPT was released from the resulting conjugate, PG-CPT, in phosphate-buffered saline with a zero-orde r kinetics in the initial 50 days. The release rates were 0.623% per day, 1 .081% per day, and 1.396% per day at pH 5.3, 7.4, and 9.0, respectively. In vitro, PG-CPT was less potent in inhibiting cell growth than was free CPT in all human tumor cell lines tested. However, PG-CPT showed better antitum or activity and tolerability than did CPT in vivo. When H322 human lung tum or cells were inoculated subcutaneously in nude mice, PG-CPT delayed the gr owth of these well-established tumors with an absolute growth delay of 32 d ays when given as 4 doses with 4-day intervals between injections at an equ ivalent CPT dose of 40 mg/kg. When H322 cells were inoculated intratracheal ly in nude mice, 5 doses of intravenous injection of PG-CPT at an equivalen t CPT dose of 10 mg/kg on days 4, 8, 12, 16, and 20 after inoculation signi ficantly prolonged the median survival of treated mice, averaging 1.8-fold that of untreated mice (p=0.01). Increasing the dose of PG-CPT to an equiva lent CPT dose of 40 mg/kg per injection administered in 4 doses on days 4, 8, 12, and 16 prolonged the median survival of treated mice by 4-fold (p=0. 0008). Significantly, mice with intratracheally inoculated H322 tumors were resistant to both CPT and cisplatin treatments. These studies demonstrated that PG may be used as an effective solubilizing carrier for CPT and that PG-CPT may have potential application in the treatment of lung cancer.