title: Activity of intoplicine (RP60475), a new DNA topoisomerase I and II inhibitor, against human tumor colony-forming units in vitro.
abstract: BACKGROUND
  Intoplicine (RP60475) is the most active analogue evaluated in the 7H-benzo[e]-pyrido-[4,3-b]-indole series of antineoplastic compounds. It exerts its activity through inhibition of DNA topoisomerase I and II.
  
  
  OBJECTIVE
  This study was planned to determine plasma concentrations of intoplicine necessary for optimal clinical antitumor activity, as well as to pinpoint possible responsive tumor types that can be included in phase II clinical studies.
  
  
  METHODS
  Tumor specimens were collected from patients as part of routine clinical measures. Single-cell suspensions were prepared from freshly obtained solid tumor biopsy specimens and were exposed to intoplicine either for 1 hour or continuously. The sensitivity of these specimens to intoplicine was evaluated in a human tumor soft-agar cloning assay. Response was considered positive when the colony-forming unit count in drug-treated samples was 50% or less than the response of control tumor samples treated with saline.
  
  
  RESULTS
  With 1-hour exposure to intoplicine at final concentrations of 2.5 micrograms/mL and 10.0 micrograms/mL, 26% and 54% of the assessable specimens showed positive in vitro responses, respectively. With continuous exposure to intoplicine at concentrations of 0.25 micrograms/mL and 2.5 micrograms/mL, 16% and 71% of the assessable specimens showed positive responses, respectively. Activity was seen against breast (71%), non-small-cell lung (69%), and ovarian (45%) cancer colony-forming units at a intoplicine concentration of 10.0 micrograms/mL after 1-hour exposure. Incomplete cross-resistance with doxorubicin, cisplatin, fluorouracil, 4-hydroperoxycyclophosphamide, vinblastine, and etoposide was also observed.
  
  
  CONCLUSIONS
  Intoplicine appears to be active in vitro against a variety of human tumors, including a subgroup of tumors insensitive in vitro to standard antineoplastic compounds. If plasma levels of 10.0 micrograms/mL can be achieved in subjects in ongoing clinical trials, intoplicine could have significant clinical activity.
  
  
  CONCLUSIONS
  These data indicate that further investigation of intoplicine is warranted.
authors.affiliation: University of Texas Health Science Center at San Antonio.
authors.forename: J R
authors.initials: JR
authors.lastname: Eckardt
authors.forename: H A
authors.initials: HA
authors.lastname: Burris
authors.forename: J G
authors.initials: JG
authors.lastname: Kuhn
authors.forename: M C
authors.initials: MC
authors.lastname: Bissery
authors.forename: M
authors.initials: M
authors.lastname: Klink-Alakl
authors.forename: G M
authors.initials: GM
authors.lastname: Clark
authors.forename: D D
authors.initials: DD
authors.lastname: Von Hoff
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011725:Pyridines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C081834:intoplicine