Thursday, November 29, 2012
An Indiana University School of Medicine
team has shown that the diabetes drug Januvia sitagliptin
can enhance the recovery of hematopoietic stem and progenitor cells after
chemotherapy or radiotherapy.2 The group is now working out the
timing and dosing of the dipeptidyl
inhibitor in the new indication.
A number of proteins involved in hematopoiesis have DPP-4 truncation
sites, which are sites that are cleaved by the peptidase. Previous studies by
the Indiana team showed that DPP-4 inhibition can block this truncation and
improve a protein's activities. Thus, they wanted to see whether genetic or
pharmacological disruptions of DPP-4 would enhance recovery of hematopoietic
stem cells (HSCs) after radiation or chemotherapy.
Indeed, Dpp-4 knockout mice receiving
chemotherapy or radiotherapy showed greater hematopoietic progenitor cell (HPC)
recovery than wild-type mice receiving the same treatments. In wild-type
receiving radiation or chemotherapy,
pretreatment with Januvia increased HPC and HSC recovery in bone marrow compared with vehicle pretreatment.
Results were published in Nature Medicine.
Merck & Co. Inc. and Ono Pharmaceutical
Co. Ltd. market Januvia to treat type 2 diabetes.
"Our immediate ongoing efforts are focused on identifying the best
timing and dosing of sitagliptin and other DPP-4 inhibitors in mice to enhance
recovery of neutrophils and platelets after radiation, chemotherapy or stem
cell transplantation," said Hal Broxmeyer, lead author and professor of
microbiology and immunology at the Indiana University School of Medicine.
His lab's overarching efforts are focused on DPP-4 truncation. "A
number of biological molecules active on many different cells, tissues and
organs have putative DPP-4 truncation sites," he said. "Our team
wants to understand the potential implications of what the truncated molecules
may do and what DPP-4 inhibition in these systems may mean. It is our belief
that DPP-4 and its inhibition will have far-reaching implications to biology in
general, not just for hematopoiesis."
The university has filed for patents covering the use of DPP-4
inhibitors to improve recovery of neutrophils and platelets after radiation,
chemotherapy or stem cell transplantation. The findings are not licensed. -TB