Optimizing and predicting the in vivo activity of AT9283 as a monotherapy and in combination with paclitaxel.
OBJECTIVE
This study aims in optimizing and predicting the in-vivo activity of AT9283 as a monotherapy and evaluating its combination with paclitaxel.


METHODS
The effectiveness of AT9283 was examined in several mouse models engrafted with BCR-ABL(+) leukemic, human multiple myeloma (MM), and human colorectal carcinoma (HCT116) cells. Dose modeling was performed by analyzing previously published data of AT9283 cancer growth inhibition in vivo. The effects of 2 cycles (7.5-12.5 mg/kg AT9283 twice daily, 5 days/week), 4 cycles (45 mg/kg AT9283 once daily, twice/week), and 3 cycles (10 mg/kg AT9283 twice daily for 5 days or 12.5 mg/kg paclitaxel once/week followed by 5 mg/kg AT9283 twice daily for 4 days) on xenograft growth were quantified to identify the energy yield associated with the different doses.


RESULTS
The continuous infusion regimens (5 days/week) used in the mice engrafted with BCR-ABL+ cells were more efficient than the regimens with twice weekly drug administration used in the mice engrafted with MM cells. The energy yield of the treatment regimen used in the BCR-ABL(+) model was perfectly correlated (r = 1) with the AT9283 dose logarithm. An efficient dose-energy model with a perfect fit (R (2) = 1) estimating the energy yield achieved by the different AT9283 doses in optimal regimens was established with the aim of being able to administer patient-specific AT9283 doses. In the HCT116 model, the predicted response to AT9283 monotherapy was nearly identical to the actual response. The regimen combining paclitaxel (1050 mg/L) with low-dose AT9283 (3360 mg/L) used in the HCT116 model was equivalent to an optimal regimen of a higher dose of AT9283 (11,332 mg/L) alone.


CONCLUSIONS
Administering AT9283 via continuous infusion optimizes treatment, while combining it with paclitaxel significantly reduces the required AT9283 dose for the advanced-stage tumors with low mitotic index.
Department of Engineering, Ain Shams University, 217 Alhegaz Street, Alnozha, 11351, Cairo, Egypt. emadmoawad@hotmail.com.
Emad Y
http://orcid.org/0000-0003-0248-2050
EY
Moawad
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004359:Drug Therapy, Combination; D006801:Humans; D020014:K562 Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
C535237:1-cyclopropyl-3-(3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl)urea; D000972:Antineoplastic Agents, Phytogenic; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D014508:Urea; D017239:Paclitaxel
AT9283; Aurora kinases; Dose-energy model; Mitotic index; Paclitaxel