title: Preclinical results of camptothecin-polymer conjugate (IT-101) in multiple human lymphoma xenograft models.
abstract: 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.
authors: Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope, City of Hope Comprehensive Cancer Center, Duarte, California, USA.
authors: Tontanai
authors: T
authors: Numbenjapon
authors: Jianyi
authors: J
authors: Wang
authors: David
authors: D
authors: Colcher
authors: Thomas
authors: T
authors: Schluep
authors: Mark E
authors: ME
authors: Davis
authors: Julienne
authors: J
authors: Duringer
authors: Leo
authors: L
authors: Kretzner
authors: Yun
authors: Y
authors: Yen
authors: Stephen J
authors: SJ
authors: Forman
authors: Andrew
authors: A
authors: Raubitschek
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D003505:Cyclodextrins; C542292:IT-101; D011108:Polymers; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D002166:Camptothecin