PURPOSE: 20(S)-Camptothecin (CAM), topotecan (TPT, active ingredient in Hycamtin) and 9-amino-20(S)-camptothecin (9AC) are topoisomerase I inhibitors that cause similar dose-limiting toxicities to rapidly renewing tissues, such as hematopoietic tissues, in humans, mice, and dogs. However, dose-limiting toxicity occurs at tenfold lower doses in humans than in mice. The purpose of the current study was to determine whether hematopoietic progenitors of the myeloid lineage from humans, mice, and dogs exhibit the differential sensitivity to these compounds that is evident in vivo. METHODS: Drug-induced inhibition of in vitro colony formation by a myeloid progenitor in human, murine, and canine marrow colony-forming unit-granulocyte/macrophage (CFU-GM) provided the basis for interspecies comparisons at concentrations which inhibited colony formation by 50% (IC50) and 90% (IC90). RESULTS: Murine IC90 values were 2.6-, 2.3-, 10-, 21-, 5.9-, and 11-fold higher than human values for CAM lactone (NSC-94600) and sodium salt (NSC-100880), TPT (NSC-609699), and racemic (NSC-629971), semisynthetic and synthetic preparations (NSC-603071) of 9AC, respectively. In contrast, canine IC90 values were the same as, or lower than, the human IC90 values for all six compounds. CONCLUSIONS: The greater susceptibility of humans and dogs to the myelotoxicity of camptothecins, compared to mice, was evident in vitro at the cellular level. Differential sensitivity between murine and human myeloid progenitors explains why the curative doses of TPT and 9AC in mice with human tumor xenografts are not achievable in patients. Realizing the curative potential of these compounds in humans will require the development of therapies to increase drug tolerance of human CFU-GM at least to a level equal to that of murine CFU-GM. Because these interspecies differences are complicated by species-specific effects of plasma proteins on drug stability, not all in vitro assay conditions will yield results which can contribute to the development of such therapies.
PURPOSE: 20(S)-Camptothecin (CAM), topotecan (TPT, active ingredient in Hycamtin) and 9-amino-20(S)-camptothecin (9AC) are topoisomerase I inhibitors that cause similar dose-limiting toxicities to rapidly renewing tissues, such as hematopoietic tissues, in humans, mice, and dogs. However, dose-limiting toxicity occurs at tenfold lower doses in humans than in mice. The purpose of the current study was to determine whether hematopoietic progenitors of the myeloid lineage from humans, mice, and dogs exhibit the differential sensitivity to these compounds that is evident in vivo. METHODS: Drug-induced inhibition of in vitro colony formation by a myeloid progenitor in human, murine, and canine marrow colony-forming unit-granulocyte/macrophage (CFU-GM) provided the basis for interspecies comparisons at concentrations which inhibited colony formation by 50% (IC50) and 90% (IC90). RESULTS:Murine IC90 values were 2.6-, 2.3-, 10-, 21-, 5.9-, and 11-fold higher than human values for CAMlactone (NSC-94600) and sodium salt (NSC-100880), TPT (NSC-609699), and racemic (NSC-629971), semisynthetic and synthetic preparations (NSC-603071) of 9AC, respectively. In contrast, canine IC90 values were the same as, or lower than, the human IC90 values for all six compounds. CONCLUSIONS: The greater susceptibility of humans and dogs to the myelotoxicity of camptothecins, compared to mice, was evident in vitro at the cellular level. Differential sensitivity between murine and human myeloid progenitors explains why the curative doses of TPT and 9AC in mice with humantumor xenografts are not achievable in patients. Realizing the curative potential of these compounds in humans will require the development of therapies to increase drug tolerance of human CFU-GM at least to a level equal to that of murine CFU-GM. Because these interspecies differences are complicated by species-specific effects of plasma proteins on drug stability, not all in vitro assay conditions will yield results which can contribute to the development of such therapies.
Authors: Shrikanta Chattopadhyay; Alison L Stewart; Siddhartha Mukherjee; Cherrie Huang; Kimberly A Hartwell; Peter G Miller; Radhika Subramanian; Leigh C Carmody; Rushdia Z Yusuf; David B Sykes; Joshiawa Paulk; Amedeo Vetere; Sonia Vallet; Loredana Santo; Diana D Cirstea; Teru Hideshima; Vlado Dančík; Max M Majireck; Mahmud M Hussain; Shambhavi Singh; Ryan Quiroz; Jonathan Iaconelli; Rakesh Karmacharya; Nicola J Tolliday; Paul A Clemons; Malcolm A S Moore; Andrew M Stern; Alykhan F Shamji; Benjamin L Ebert; Todd R Golub; Noopur S Raje; David T Scadden; Stuart L Schreiber Journal: Cell Rep Date: 2015-02-05 Impact factor: 9.423
Authors: Shanbao Cai; Haiyan Wang; Barbara Bailey; Aaron Ernstberger; Beth E Juliar; Anthony L Sinn; Rebecca J Chan; David R Jones; Lindsey D Mayo; Arthur R Baluyut; W Scott Goebel; Karen E Pollok Journal: Clin Cancer Res Date: 2011-04-12 Impact factor: 12.531
Authors: Haiyan Wang; Shanbao Cai; Barbara J Bailey; M Reza Saadatzadeh; Jixin Ding; Eva Tonsing-Carter; Taxiarchis M Georgiadis; T Zachary Gunter; Eric C Long; Robert E Minto; Kevin R Gordon; Stephanie E Sen; Wenjing Cai; Jacob A Eitel; David L Waning; Lauren R Bringman; Clark D Wells; Mary E Murray; Jann N Sarkaria; Lawrence M Gelbert; David R Jones; Aaron A Cohen-Gadol; Lindsey D Mayo; Harlan E Shannon; Karen E Pollok Journal: J Neurosurg Date: 2016-05-13 Impact factor: 5.115
Authors: Thomas L Horn; J Brooks Harder; William D Johnson; Patrick T Curry; Ralph E Parchment; Robert L Morrissey; Paul W Mellick; Karim A Calis; Philip W Gold; Kenner C Rice; Carlo Contoreggi; Dennis S Charney; Giovanni Cizza; Elizabeth R Glaze; Joseph E Tomaszewski; David L McCormick Journal: Toxicology Date: 2008-03-13 Impact factor: 4.221