Gn. Thalmann et al., SURAMIN-INDUCED DECREASE IN PROSTATE-SPECIFIC ANTIGEN EXPRESSION WITHNO EFFECT ON TUMOR-GROWTH IN THE LNCAP MODEL OF HUMAN PROSTATE-CANCER, Journal of the National Cancer Institute, 88(12), 1996, pp. 794-801
Background: Suramin, a polysulfonated naphthylurea and a recognized an
titrypanosomal agent, has shown some promise in phase II clinical tria
ls in the management of hormone-refractory human prostate cancer. Redu
ction of serum prostate-specific antigen (PSA) levels has been propose
d as an end point for evaluating the antitumor efficacy of treatments
for hormone-refractory prostate cancer. Purpose: We examined the antit
umor effect of suramin in an in vivo mouse model of hormone-refractory
human prostate cancer to determine whether a decrease in PSA levels r
eflects a reduction in tumor growth (volume). The tumors were induced
in castrated, athymic nude mice by use of the androgen-independent, tu
morigenic human prostate cancer cell line C4-2, which is a subline of
the androgen-dependent, parental nontumorigenic cell line LNCaP. We al
so evaluated the effects of suramin in vitro on cell growth and the ex
pression of PSA messenger RNA (mRNA) in both LNCaP and C4-2 cells. Met
hods: For the in vivo studies, 24 mice were given a subcutaneous injec
tion of 5 x 10(6) C4-2 cells at each of four sites. Animals (n = 20) w
ith tumor volumes greater than 1 mm(3) or less than 5 mm(3) were divid
ed equally into two groups. Drug treatment was initiated in one group
by administration of 1 mg suramin intraperitoneally, followed by 0.1 m
g suramin at 10-day intervals to maintain constant serum levels. Tumor
growth and PSA expression levels were monitored. For the in vitro stu
dies, both LNCaP and C4-2 cells were exposed to 100-400 mu g/mL surami
n, and cell growth was monitored by a quantitative crystal violet assa
y. PSA mRNA expression was assessed by northern blot analysis in cells
treated with either 250 mu g/mL suramin, 400 ng/mL dihydrotestosteron
e (DHT) (positive control), or 0.5-75 mu g/mL hydrocortisone (to mimic
the clinical use of hydrocortisone during suramin treatment to compen
sate for the loss of adrenocortical function). In some studies, the co
mbined effect of DHT and suramin on PSA mRNA expression was also evalu
ated. A two-way analysis of variance was performed to evaluate the tre
atment differences, and P values were obtained from two-sided tests fo
r statistical significance. Results: In vivo, suramin did not signific
antly affect the growth of androgen-independent C4-2 tumors (relative
to the growth of tumors in 5% glucose-treated control animals; P = .76
). However, suramin significantly decreased the ratio of PSA level to
tumor volume (ng/mL PSA per mm(3) of tumor) (P<.001). Mice developed b
one metastases in both treatment arms. Suramin affected the in vitro g
rowth of LNCaP cells but not of C4-2 cells. Suramin diminished PSA mRN
A expression in both LNCaP and C4-2 cells grown in vitro. Hydrocortiso
ne had no effect on PSA mRNA levels. Conclusions: Although suramin inh
ibited the growth of androgen-dependent LNCaP cells, it did not inhibi
t the growth of androgen-independent C4-2 cells either in vitro or in
vivo. Suramin significantly decreased PSA mRNA expression in both cell
lines in vitro and depressed serum PSA levels in mice bearing androge
n-independent C4-2 tumors. Implications: PSA level should be used with
caution as an end point in clinical trials using suramin therapy for
hormone-refractory prostate cancer.