Since several anticancer drugs are known to become more cytotoxic to cells in an acidic milieu, we have attempted to utilize the
carbonic anhydrase inhibitor,
Acetazolamide, to acidify the blood and
tumor of C3H mice bearing the FSaIIC
fibrosarcoma in order to sensitize
tumor cells in vivo to CDDP,
Melphalan,
BCNU,
SR4233 or
PtCl4 (Fast Black)2 +/-
hyperthermia. The direct cytotoxic interactions between the anticancer drugs and
Acetazolamide were tested in FSaIIC cells in vitro with the monacidifying
diuretic Chlorothrozide as a control. When cells were exposed to CDDP both
diuretics protected against cytotoxicity in a dose dependent fashion. In contrast, cells exposed to
Melphalan were minimally sensitized and those exposed to
BCNU,
SR4233, or
PtCl4 (Fast Black)2 were essentially unaffected by the presence of the
diuretic agents. Both
diuretics were essentially non-toxic to cells in vitro, and, interestingly, both drugs markedly protected cells against
hyperthermia under low pH conditions. In vitro, however, Acetzolamide produced a
tumor growth delay of 2.3 days alone when given
at 10 mg/kg i.p. once (the most effective dose) and produced additive growth delays with CDDP and
Melphalan, but probably greater than additive delays with
SR4233 and
PtCl4 (Fast Black)2. When
Acetazolamide was given daily for 5 days starting on the day the anticancer drugs were given once (day 7) essentially no further increase in
tumor growth delay of nearly 16 days was observed versus only 4,6 days for the
drug alone. When
hyperthermia (43 degrees C min.) was delivered locally to the
tumor after i.p. injection of the drugs, further growth delays were produced for every
drug combination which probably were additive in extent. Blood and urine pH determinations revealed that a pH drop of 1 units occurred in the blood and a pH elevation of 1 to 21 units occurred in the urine 1 hr. after i.p. injection of
Acetazolamide. These results indicate that this
carbonic anhydrase inhibitor can add to the anticancer activity of the drugs tested. The mechanism may involve its ability to acidify the intratumoral environment, but other mechanisms can not be excluded.