In vitro studies of the hyperthermic enhancement of activated ifosfamide (4-hydroperoxy-ifosfamide) and glucose isophosphoramide mustard.
OBJECTIVE
To study the effect of hyperthermia on the cytotoxicity of glucose isophosphoramide mustard (D-19575), a derivative of ifosfamide, which does not require activation and preclinically demonstrates less nephrotoxicity and myelosuppression than ifosfamide.


METHODS
In vitro studies (using a crystal violet cell survival assay) of the interaction of hyperthermia with D-19575, as well as the activated form of ifosfamide (4-hydroperoxy-ifosfamide, D-18851), were performed using L929 and OVCAR-3 cell lines held at various temperatures (i.e. 37 degrees C (control), 40.5 degrees C, 41.8 degrees C, 42.5 degrees C, and 43 degrees C) for 65 min.


RESULTS
The following thermal enhancement ratios (TER) were demonstrated: D-19575 in L929 1.2, 2.0 and 2.3 at 40.5, 41.8 and 42.5 degrees C, respectively; for D-18851 in L929 1.7 at 41.8 degrees C; for D-19575 in OVCAR-3 2.1, 3.2 and 3.3 at 40.5, 41.8 and 42.5 degrees C, respectively; for D-18851 in OVCAR-3 4.6 at 41.8 degrees C.


CONCLUSIONS
The significant observed increase in cytotoxicity of D-19575 caused by hyperthermia taken together with its known preclinical toxicity profile, encourage its further preclinical and ultimately clinical testing, including its use with whole body and regional hyperthermia.
Kutz
M E
ME
Department of Medicine, University of Wisconsin Clinical Science Center, Madison 53792, USA.
Mulkerin
D L
DL
Wiedemann
G J
GJ
Katschinski
D M
DM
Robins
H I
HI
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D005947:Glucose / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D006979:Hyperthermia, Induced; D007069:Ifosfamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C092028:beta-D-glucosylisophosphoramide mustard; D005947:Glucose; D007069:Ifosfamide