NLCQ-1, a novel hypoxic cytotoxin: potentiation of melphalan, cisDDP and cyclophosphamide in vivo.
OBJECTIVE
To investigate in vivo interactions between the recently developed bioreductive agent 4-[3-(2-nitroimidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1) and the chemotherapeutic agents melphalan (L-PAM), cis-platin (cisDDP) and cyclophosphamide (CPM).


METHODS
EMT6 and FSaIIC tumor cells were inoculated (subcutaneously) into the leg(s) of female Balb/c and male C3H mice, respectively. Treatment was initiated at 10 mm (EMT6) and 5 mm (FSaIIC) mean tumor diameter. The in vivo-in vitro and tumor regrowth assays were used, respectively, as endpoints. Bone marrow toxicity studies were also performed when the in vivo-in vitro assay was used. Drugs were given by i.p. injection. Tumors were excised 18-h after chemotherapeutic drug administration (Balb/c mice) or measured daily until three times their original size (C3H mice). The optimum administration schedule for potentiation between NLCQ-1 and each chemotherapeutic drug, as well as dose modification factors (DMF) at the optimum time, were determined with the in vivo-in vitro assay. When the tumor regrowth assay was used, each chemotherapeutic agent was given either as a single dose or as a split dose over two consecutive days at the optimum administration time after a 10 mg/kg NLCQ-1 i.p. injection.


RESULTS
NLCQ-1 (at 0.33 times MTD), strongly potentiated the antitumor effect of L-PAM, cisDDP and CPM without concurrent enhancement in bone marrow toxicity. Potentiation was strictly schedule dependent and the optimum effect (1.5 to 2 logs killing beyond additivity) was observed when NLCQ-1 was given 60-, 45-, and 110-min before L-PAM, cisDDP, and CPM, respectively. The DMF values at 30% survival were 2.5, 1.9, and 3.8 for L-PAM, cisDDP, and CPM, respectively. DMF values for bone marrow toxicity at 50% survival were ca. 1 for all chemotherapeutic drugs. Pretreatment with NLCQ-1 resulted in 4-12 days extra delay in the regrowth of FSaIIC tumors.


CONCLUSIONS
These results support the clinical investigation of NLCQ-1 as a chemosensitizer.
Papadopoulou
M V
MV
Department of Radiation Medicine, Evanston Northwestern Healthcare, IL 60201, USA. mvp499@anima.nums.nwu.edu
Ji
M
M
Bloomer
W D
WD
D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology; D003520:Cyclophosphamide / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D008297:Male; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D011355:Prodrugs / Q000494:pharmacology*
D000634:Aminoquinolines; D000970:Antineoplastic Agents; D011355:Prodrugs; D003520:Cyclophosphamide; D002945:Cisplatin; D008558:Melphalan