ACTIVITY OF PIVALOYLOXYMETHYL BUTYRATE, A NOVEL ANTICANCER AGENT, ON PRIMARY HUMAN TUMOR COLONY-FORMING-UNITS

The anti-proliferative effects of pivaloyloxymethyl butyrate (AN-9), a butyric acid (BA) derivative with potent tumor-differentiating proper ties both in vitro and in vivo, was evaluated against colorectal, brea st, lung, ovarian, renal cell, bladder, and other types of tumor colon y-forming units in a human tumor cloning assay. A total of 76 evaluabl e specimens were exposed to AN-9 continuously, 48 of these were also e xposed to BA continuously for direct comparison of the two agents, and 20 specimens were exposed to AN-9 for two hours. An ill vitro inhibit ory response was defined as a greater than or equal to 50% decrease in tumor colony formation in treated cells compared to untreated control s. Superior anti-tumor activity was observed with the continuous expos ure to AN-9 (39% in vitro response at 100 mu M and 70% at 200 mu M) th an with the two-hour exposure (20% at 100 mu M and 25% at 200 mu M). A t a continuous concentration of 200 mu M, AN-9 demonstrated greater tu mor-specific activity than BA against melanoma (100% vs. 67%), ovarian (67% vs. 40%), breast (63% vs. 0%), non-small cell lung (60% vs. 10%) , and colorectal tumor colony-forming units (62% vs. 20%). AN-9 is a n ovel differentiating agent with activity against colony-forming units derived from a variety of primary human tumors, including those that a re considered relatively chemoresistant, and may thus provide a therap eutic alternative or addition to standard cytotoxic agents, if appropr iate drug concentrations can be achieved in patients.