Preclinical results of camptothecin-polymer conjugate (IT-101) in multiple human lymphoma xenograft models.
OBJECTIVE
Camptothecin (CPT) has potent broad-spectrum antitumor activity by inhibiting type I DNA topoisomerase (DNA topo I). It has not been used clinically because it is water-insoluble and highly toxic. As a result, irinotecan (CPT-11), a water-soluble analogue of CPT, has been developed and used as salvage chemotherapy in patients with relapsed/refractory lymphoma, but with only modest activity. Recently, we have developed a cyclodextrin-based polymer conjugate of 20-(S)-CPT (IT-101). In this study, we evaluated the preclinical antilymphoma efficacy of IT-101 as compared with CPT-11.


METHODS
We determined an in vitro cytotoxicity of IT-101, CPT-11, and their metabolites against multiple human lymphoma cell lines. In human lymphoma xenografts, the pharmacokinetics, inhibitions of tumor DNA topo I catalytic activity, and antilymphoma activities of these compounds were evaluated.


RESULTS
IT-101 and CPT had very high in vitro cytotoxicity against all lymphoma cell lines tested. As compared with CPT-11 and SN-38, IT-101 and CPT had longer release kinetics and significantly inhibit higher tumor DNA topo I catalytic activities. Furthermore, IT-101 showed significantly prolonged the survival of animals bearing s.c. and disseminated human xenografts when compared with CPT-11 at its maximum tolerated dose in mice.


CONCLUSIONS
The promising present results provide the basis for a phase I clinical trial in patients with relapsed/refractory lymphoma.
Numbenjapon
Tontanai
T
Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope, City of Hope Comprehensive Cancer Center, Duarte, California, USA.
Wang
Jianyi
J
Colcher
David
D
Schluep
Thomas
T
Davis
Mark E
ME
Duringer
Julienne
J
Kretzner
Leo
L
Yen
Yun
Y
Forman
Stephen J
SJ
Raubitschek
Andrew
A
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003505:Cyclodextrins / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011108:Polymers / Q000737:chemistry / Q000627:therapeutic use; D059004:Topoisomerase I Inhibitors; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D003505:Cyclodextrins; C542292:IT-101; D011108:Polymers; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin