title: Rational combination therapy of vintafolide (EC145) with commonly used chemotherapeutic drugs.
abstract: OBJECTIVE
  When evaluated in patients with ovarian and other cancer, vintafolide (EC145), a potent folate-targeted vinca alkaloid conjugate, displayed a toxicity profile that seemed to be nonoverlapping with many standard-of-care cancer therapeutics. It was, therefore, hypothesized that combining vintafolide with certain approved anticancer drugs may afford greater therapeutic efficacy compared with single-agent therapy. To explore this concept, vintafolide was evaluated in combination with pegylated liposomal doxorubicin (PLD; DOXIL), cisplatin, carboplatin, paclitaxel, docetaxel, topotecan, and irinotecan against folate receptor (FR)-positive models.
  
  
  METHODS
  FR-expressing KB, M109, IGROV, and L1210 cells were first exposed to graded concentrations of vintafolide, either alone or in combination with doxorubicin (active ingredient in PLD), and isobologram plots and combination index values generated. The vintafolide combinations were also studied in mice bearing various FR-expressing tumors.
  
  
  RESULTS
  Vintafolide displayed strong synergistic activity against KB cells when combined with doxorubicin, and no less-than-additive effects resulted when tested against M109, IGROV, and L1210 cells. In contrast, when either desacetylvinblastine hydrazide (DAVLBH; the vinca alkaloid moiety in vintafolide) or vindesine (the vinca alkaloid most structurally similar to DAVLBH) were tested in combination with doxorubicin, less-than-additive antitumor effects were observed. In vivo, all vintafolide drug combinations produced far greater antitumor effect (complete responses and cures) compared with the single agents alone, without significant increase in overall toxicity. Importantly, these benefits were not observed with combinations of PLD and DAVLBH or vindesine.
  
  
  CONCLUSIONS
  On the basis of these encouraging preclinical results, clinical studies to evaluate vintafolide drug combination therapies are now under way.
authors.affiliation: Authors' Affiliation: Endocyte Inc., West Lafayette, Indiana.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Reddy
authors.forename: Ryan
authors.initials: R
authors.lastname: Dorton
authors.forename: Alicia
authors.initials: A
authors.lastname: Bloomfield
authors.forename: Melissa
authors.initials: M
authors.lastname: Nelson
authors.forename: Marilynn
authors.initials: M
authors.lastname: Vetzel
authors.forename: John
authors.initials: J
authors.lastname: Guan
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Leamon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D005492:Folic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D000077146:Irinotecan; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology; D019772:Topotecan / Q000008:administration & dosage / Q000494:pharmacology; D016896:Treatment Outcome; D014748:Vinca Alkaloids / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C520389:EC145; D043823:Taxoids; D014748:Vinca Alkaloids; D000077143:Docetaxel; D000077146:Irinotecan; D019772:Topotecan; D004317:Doxorubicin; D005492:Folic Acid; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin; D002166:Camptothecin