Autologous Bone Marrow Transplantation - Blog Science Connections

Acetaldophosphamide Ex Vivo Chemotherapy 169
aldehyde dehydrogenase-mediated detoxification described for 4-HC (4)
remains to be determined.
Our studies revealed A-ALD's profound antileukemic effect on leukemic
clonogeneic cells, with an ex vivo therapeutic ratio of two to two and one-half
times that of normal marrow CFUs-GM. Moreover, we have shown absence of
cross-resistance to doxorubicin. This is an important property, considering that
many leukemic cells have been exposed to anthracyclines during chemotherapy
in vivo preceding marrow collection for autologous rescue. In contrast to 4-HC,
A-ALD can be easily prepared in bulk quantities, and it is highly stable in neutral
buffer solutions with a half-life of 52 hours at pH 7.2 and 37°C, a property of
considerable importance for ex vivo chemotherapy procedures. A-ALD is
converted into its active form by esterases; whether the presence of such an
activation step might further add to the selectivity of its action remains to be
determined. After activation into aldophosphamide it exists in equilibrium with
4-HC, and its major metabolites are phosphorodiamidic mustard and acrolein.
Like 4-HC, its toxicity might be modulated by aldehyde dehydrogenasemediated
detoxification, a possibility which is currently being investigated.
In conclusion, A-ALD is a novel, stable aldophosphamide analogue that is
active in vitro with significant antileukemic potential and sparing effect on
primitive CFCl-GM progenitors (stem cells?). It holds significant potential for ex
vivo chemotherapy of marrow used for autologous bone marrow transplantation.
REFERENCES
1. Beran M, Zander AR. Proceedings of the American Association for Cancer Research
1984;25:377 (abstract).
2. Beran M, Zander AR, McCredie KB. Scand J Haematol (in press).
3. Herve P, Tamayo E, Peters A. Br J Haematol 1983;53:638.
4. Kohn FR, Sladek N. Biochem Pharmacol 1985;34:3465.