Hepatoma 8999 was sensitive to
Lycurim [1,4-di-(methylsulfonyloxy-ethylamino)-1,4-dideoxy-ms-
erythritol] with a mean lethal dose (LD50) of 8.1 X 10(-8) M for a 6-hour treatment in vitro. The
drug dose lethal to 10% of the rats with
Lycurim (10 mg/kg) injected ip 12 times into
hepatoma 8999-bearing BUF rats at 10-day intervals provided a mean increase in life-span (ILS) of 156%. The more rapidly growing, less differentiated
hepatoma 3924A was tenfold less sensitive to
Lycurim in vitro, and three treatments in vivo (10 mg/kg given every 8 days) gave an ILS of only 18% in ACI/N rats. Because
hepatoma 8999 had a high
adenosine kinase activity, the effect of
Pyrazofurin (
PF; 3-beta-D-ribofuranosyl-4-hydroxypyrazole-5-carboxamide) was examined in vitro: The LD50 was 8.5 X 10(-8) M in a 6-hour exposure. In
hepatoma 3924A, with a fifteenfold lower
adenosine kinase, the LD50 was 22-fold higher. Three treatments with PF (4 mg/kg given every 2 days) in
hepatoma 8999 caused an 18% ILS and no host toxicity, but in
hepatoma 3924A no significant ILS was observed.
Lycurim combined with PF (0.05 microM each) in
hepatoma 8999 cells in vitro provided synergistic kill, but
Lycurim and PF (0.3 and 1 microM, respectively) in
hepatoma 3924A cells yielded summation. When 10 rats with
hepatoma 8999 were treated 15 times with the optimal dose of
Lycurim (7.5 mg/kg every 10 1/2 days), 1-year survivors numbered 7. Alternate doses of
Lycurim (7.5 mg/kg) and
PF (3 mg/kg) at 5-day intervals for 4 months to 10 rats gave an ILS of 152% with eight 1-year survivors and no host toxicity.