Bone marrow CFU-GM and human tumor xenograft efficacy of three tubulin binding agents.
OBJECTIVE
The dynamic instability of microtubules in cells is one of the key targets of anticancer therapeutics. Microtubule-disrupting agents such as vinca alkaloids and microtubule-stabilizing agents such as taxanes are important antitumor agents. The bone marrow toxicity and human tumor xenograft activity of three tubulin-binding compounds, vincristine, paclitaxel, and tasidotin were compared.


METHODS
Mouse and human bone marrow were subjected to colony-forming (CFU-GM) assays over a 5-log concentration range in culture. In vivo, a range of tasidotin doses was compared with vincristine, paclitaxel, and docetaxel for efficacy in several human tumor xenografts.


RESULTS
The IC(90) concentrations for vincristine and paclitaxel for mouse CFU-GM were 30 and 27 nM, and for human CFU-GM were 3 and 9 nM, giving mouse to human differentials of ten- and threefold. Tasidotin produced IC(90)s of >300 nM in mouse and 65 nM in human CFU-GM, thus a >4.6-fold differential between species. In vivo, tasidotin resulted in a dose-dependent increase in tumor growth delay in the RL lymphoma, the RPMI 8226 multiple myeloma, and MX-1 breast carcinoma models. Vincristine and tasidotin were also very effective against these tumors. The PC-3 prostate carcinoma was very responsive to full-dose paclitaxel and docetaxel while tasidotin generated a dose dependent effect.


CONCLUSIONS
Bringing together bone marrow toxicity data, pharmacokinetic parameters, and human tumor xenograft efficacy provides valuable information for the translation of preclinical findings to the clinic.
Kurtzberg
Leslie S
LS
Genzyme Corporation, Framingham, MA 01701, USA. Leslie.Kurtzberg@Genzyme.com
Roth
Stephanie D
SD
Bagley
Rebecca G
RG
Rouleau
Cecile
C
Yao
Min
M
Crawford
Jennifer L
JL
Krumbholz
Roy D
RD
Schmid
Steven M
SM
Teicher
Beverly A
BA
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology; D009842:Oligopeptides / Q000008:administration & dosage / Q000627:therapeutic use*; D017239:Paclitaxel / Q000008:administration & dosage / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D014404:Tubulin / Q000187:drug effects*; D014410:Tumor Stem Cell Assay; D014750:Vincristine / Q000008:administration & dosage / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D009842:Oligopeptides; D014404:Tubulin; C504233:tasidotin; D014750:Vincristine; D017239:Paclitaxel