Inhibitory effect of 12-O-tetradecanoylphorbol-13-acetate alone or in combination with all-trans-retinoic acid on the growth of LNCaP prostate tumors in immunodeficient mice.

Clinically achievable concentrations of 12-O-tetradecanoylphorbol-13-acetate (TPA; 0.16-0.32 nM) and all-trans-retinoic acid (ATRA; 0.5-1 micro M) had a synergistic inhibitory effect on the growth of cultured LNCaP prostate cancer cells, and apoptosis was markedly stimulated. In additional studies, NCr immunodeficient mice received s.c. injection with LNCaP cells in Matrigel. After 4-6 weeks, mice with well-established tumors received i.p. injection with vehicle, TPA (0.16 nmol/g body weight), ATRA (0.5 nmol/g body weight), or TPA+ATRA in vehicle once a day for 46 days. Tumor growth occurred in all of the vehicle-treated control mice. The percentage of animals with some tumor regression after 21 days of treatment was 0% for the control group, 31% for the ATRA group, 62% for the TPA group, and 100% for the TPA+ATRA group (13 mice/group). Although treatment of the mice with TPA or TPA+ATRA continued to inhibit tumor growth for the duration of the 46-day study, treatment of the mice with ATRA alone did not inhibit tumor growth beyond 28 days of daily injections (6 mice/group). Mechanistic studies indicated that treatment of the mice with TPA or TPA+ATRA for 46 days increased apoptosis in the tumors, and treatment with TPA+ATRA also decreased the mitotic index. Because the dose of TPA used in this study was effective and resulted in clinically achievable blood levels, clinical trials with TPA alone or in combination with ATRA in patients with prostate cancer may be warranted.