Human
prostatic cancer cells have a remarkably low rate of proliferation even when they have metastasized to the bone and have become
androgen independent (Berges et al., Clin.
Cancer Res., 1:473-480, 1995). Due to this low proliferation, patients with such
androgen-independent metastatic
prostatic cancer cells are rarely treated successfully with the presently available chemotherapeutic agents. Therefore, new approaches are urgently needed which are not dependent on the rate of
cancer cell proliferation for their effectiveness. One such approach is to inhibit the angiogenic response within localized and metastatic
cancer deposits, since the resultant
hypoxia-induced
tumor cell death does not require cell proliferation. We have previously demonstrated that the
quinoline-3-carboxamide,
linomide, is an p.o. active agent which inhibits
tumor angiogenesis and thus blood flow in a variety of rat
prostatic cancers independent of their growth rate,
androgen sensitivity, or metastatic ability. Because of its antiangiogenic effects,
linomide treatment induces the hypoxic death of rat
prostatic cancer cells, thus inhibiting their net growth and
metastases. To determine whether human
prostatic cancer cells are similarly sensitive to
hypoxia-induced death caused by
linomide inhibition of
tumor angiogenesis,
androgen-independent TSU and PC-3 human
prostatic cancer cells were xenotransplanted into SCID mice that were either untreated or treated p.o. with
linomide. These studies demonstrated that
linomide treatment decreases microvessel density in both
androgen-independent human
prostatic cancers. Microvessel density was decreased from 1.8 +/- 0.4% of the total area in control
tumors to 1.0 +/- 0.2% in
linomide-treated TSU
tumors [i.e., a 44% decrease in microvessel density (P < 0.05)]. Similarly, a 56% decrease (P < 0.05) was observed in the microvessel density of PC-3
tumors (i.e., 2.7 +/- 0.8% of the area in control
tumor versus 1.2 +/- 0.2% in the
linomide-treated
tumors). This inhibition of angiogenesis increased cell death in both TSU and PC-3
cancer cells. This is reflected in both an increase in the area of
necrosis and an increase in the apoptotic index in non-necrotic areas. In untreated TSU
tumors, 40 +/- 2% of
tumor volume was necrotic.
Linomide treatment increased this necrotic percentage to 59 +/- 2% [i.e., 48% increase (P < 0.05)].
Linomide therapy also increased apoptotic cell death in non-necrotic
tumor areas. In the untreated TSU
tumors, 2.9 +/- 0.6% of
tumor cells were apoptotic in the non-necrotic areas, and in the
linomide-treated TSU
tumors this percentage increased to 3.6 +/- 0.4% [i.e., 24% increase (P < 0.05)].(ABSTRACT TRUNCATED AT 400 WORDS)