Clinically achievable concentrations of 12-O-tetradecanoylphorbol-13-acetate (TPA; 0.16-0.32 nM) and all-trans retinoic acid (ATRA; 0.5-1 μM) 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 were injected subcutaneously with LNCaP cells in matragel. After 4-6 weeks, mice with well-established tumors were injected i.p. with vehicle or with TPA (0.16 nmol/g body weight), ATRA (0.5 nmol/g body weight) or with TPA+ATRA in vehicle once a day for 46 days. Tumor growth occurred in all of the vehicle-treated control mice. The percent 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). These treatments were less effective when continued beyond 21 days (6 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. 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. Since 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. Supported in part by grants from the Dean and Betty Gallo Prostate Cancer Center (Cancer Institute of New Jersey) and the National Institutes of Health (CA 092268 and ES 05022).
[Proc Amer Assoc Cancer Res, Volume 45, 2004]