Effectiveness of water soluble poly(L-glutamic acid)-camptothecin conjugate against resistant human lung cancer xenografted in nude mice.
A camptothecin (CPT) formulation that can be easily administered, is less toxic, and has greater antitumor effect is needed. In this study, a water-soluble CPT derivative was obtained by direct coupling of CPT to poly(L-glutamic acid) (PG) through the C20(S)-hydroxyl group. CPT was released from the resulting conjugate, PG-CPT, in phosphate-buffered saline with a zero-order 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 antitumor activity and tolerability than did CPT in vivo. When H322 human lung tumor cells were inoculated subcutaneously in nude mice, PG-CPT delayed the growth of these well-established tumors with an absolute growth delay of 32 days when given as 4 doses with 4-day intervals between injections at an equivalent CPT dose of 40 mg/kg. When H322 cells were inoculated intratracheally in nude mice, 5 doses of intravenous injection of PG-CPT at an equivalent CPT dose of 10 mg/kg on days 4, 8, 12, 16, and 20 after inoculation significantly 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 equivalent 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.
Zou
Y
Y
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Wu
Q P
QP
Tansey
W
W
Chow
D
D
Hung
M C
MC
Charnsangavej
C
C
Wallace
S
S
Li
C
C
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000627:therapeutic use*; D002166:Camptothecin / Q000737:chemistry / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use*; D011099:Polyglutamic Acid / Q000737:chemistry / Q000627:therapeutic use* / Q000031:analogs & derivatives; D012995:Solubility; D043823:Taxoids; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D004338:Drug Combinations; D043823:Taxoids; D011099:Polyglutamic Acid; D017239:Paclitaxel; C509139:paclitaxel poliglumex; D002166:Camptothecin