Comparison of different busulfan analogues for depletion of hematopoietic stem cells and promotion of donor-type chimerism in murine bone marrow transplant recipients
Gr. Westerhof et al., Comparison of different busulfan analogues for depletion of hematopoietic stem cells and promotion of donor-type chimerism in murine bone marrow transplant recipients, CANCER RES, 60(19), 2000, pp. 5470-5478
Busulfan (1,4-butanediol dimethanesulfonate, BU) is relatively unique among
other standard chemotherapy compounds in its ability to deplete noncycling
primitive stem cells in the host and consequently to allow for high levels
of long-term, donor-type engraftment after bone marrow transplantation (BM
T), Such a property explains why this drug can be used as an alternative to
total body irradiation in preparative regimes for BMT, However, as with ra
diation, BU conditioning is still troubled by severe toxicities that limit
its applications to suboptimal drug doses. These problems stress the need f
or other BMT-conditioning drugs that are better tolerated and more selectiv
ely targeted toward normal and malignant hematopoietic stem cells. We have
therefore compared the effects of various novel dimethanesulfonate compound
s (related to BU) in terms of their toxicity to different stem cell subsets
in vivo and in vitro and their ability to provide for long-term donor bone
marrow engraftment using the congenic glucose-6-phosphate isomerase type 1
marker. Introduction of a benzene or cyclohexane ring in some of these dru
gs affords rigidity to the molecule and restricts the spatial positioning o
f the alkylating groups, Among 25 different compounds thus far tested at si
ngle doses, PL63 [cis-1,2-(2-hydroxyethyl) cyclohexane dimethanesulfonate]
proved to be the most effective in providing for hematopoietic engraftment,
The trans-isomer of the same compound gave significantly less engraftment
and was comparable with the effects of dimethylbusulfan and Hepsulfam. The
engraftment data correlated well with the depletion of different bone marro
w stem cell subsets in the host as measured using the cobblestone area form
ing cell assay. The extent of stem cell depletion could not be explained on
the basis of the distance and orientation of the two alkylating groups. Ph
armacokinetic data, however, indicate that there is a correlation between b
iological activity and plasma levels reached,
The diverse cytotoxic effects shown by these novel analogues of BU have pro
vided a basis for relating biological activity with pharmacokinetic propert
ies rather than with structural properties such as distance and orientation
of the two alkylating groups, The identification of highly active compound
s such as PL63 offers an opportunity for further developing other closely r
elated drugs for potential application in clinical BMT conditioning therapy
.