Camptothecin delivery systems: the antitumor activity of a camptothecin-20-0-polyethylene glycol ester transport form.
BACKGROUND
This study was designed to assess the efficacy of polyethylene glycol(PEG) conjugated camptothecin, PEG-alpha-camptothecin, a novel water soluble transport form (prodrug) of the naturally derived antitumor drug, 20-(S)-camptothecin.


METHODS
Circulatory retention studies were performed in non-tumor bearing mice injected intravenously with 300 mg/kg of PEG-alpha-camptothecin. Therapeutic efficacy was evaluated in both a murine P388/0 leukemia and a colorectal HT-29 carcinoma xenograft model.


RESULTS
PEG-alpha-camptothecin had a blood t1/2 alpha of less than 5 minutes and a t1/2 beta of 3.5 hours. Five intraperitoneal injections of 3.2 mg/kg/day 20-(S)-camptothecin equivalents of PEG-alpha-camptothecin in our leukemia model resulted in significant survival over untreated controls (P < 0.001), with a mean time to death of treated versus control (T/C ratio) of 2.94 and a cure rate of 80% (n = 20). The colorectal carcinoma xenograft model demonstrated that 2-3 mg/kg/day 20-(S)-camptothecin equivalents of PEG-alpha-camptothecin given 5 days a week for 5 weeks could reduce an initial tumor burden of 300 mm3 by more than 90% without any signs of overt toxicity.


CONCLUSIONS
This water soluble transport form of 20-(S)-camptothecin and its underlying technology may have clinical application.
Conover
C D
CD
Research and Development, Enzon Inc., Piscataway, NJ 08854, USA.
Pendri
A
A
Lee
C
C
Gilbert
C W
CW
Shum
K L
KL
Greenwald
R B
RB
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001835:Body Weight / Q000187:drug effects; D002166:Camptothecin / Q000008:administration & dosage*; D015179:Colorectal Neoplasms / Q000188:drug therapy; D005260:Female; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014677:Pharmaceutical Vehicles; D011092:Polyethylene Glycols; D011355:Prodrugs; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D014677:Pharmaceutical Vehicles; D011355:Prodrugs; D011092:Polyethylene Glycols; D002166:Camptothecin