Previous investigations have shown that combining the
radiation sensitizer misonidazole with conventional alkylating chemotherapeutic agents can lead to a therapeutic advantage. More recently, another sensitizer,
RSU 1069, has been reported to give an enhancement of
antitumor agent efficacy similar to that observed with
misonidazole, but at an approximately tenfold lower sensitizer dose. One chemotherapeutic agent whose activity has been modified by sensitizers to a greater extent in
tumors than in critical normal tissues is the nitrosourea
lomustine (
CCNU). The present studies evaluated the therapeutic benefit of combining
RSU 1069 and
CCNU in KHT
sarcoma-bearing C3H/HeJ mice. The drugs were administered ip, and
tumor response was assessed by measuring the survival of clonogenic KHT cells 22-24 hours
after treatment. Normal tissue toxicity was determined using peripheral wbc counts 3 days
after treatment and a 30-day lethality assay. Combining
CCNU with a 0.38-mmol/kg dose of
RSU 1069 increased
tumor cell killing by
a factor of approximately 1.9. Wbc toxicity and 30-day animal lethality increased with
CCNU dose, but the addition of
RSU 1069 enhanced either endpoint only slightly (factor of 1.0-1.2). The addition of
RSU 1069 to
CCNU treatment, therefore, led to a significant therapeutic benefit.