Abstract

The antiandrogen flutamide and the 5α-reductase inhibitor finasteride were administered twice daily at a dose of 1 mg alone or in combination in mice bearing androgen-sensitive Shionogi tumors, a model predictive of androgen-sensitive prostate cancer in men. Intact or orchiectomized animals were supplemented with an implant of androstenedione in order to mimic the contribution of androgens of adrenal origin in men. Treatment for 20 days with flutamide alone caused 28% and 36% decreases in tumor size and prostatic weight respectively, whereas finasteride alone caused 18% and 16% inhibitions of the same parameters. On the other hand, combination of the two compounds inhibited the value of the same parameters by 43% and 58%. In orchiectomized animals also implanted with androstenedione, flutamide alone caused 35% and 39% decreases in tumor growth and prostatic weight respectively, whereas finasteride alone caused respective 27% and 15% inhibitions, and combination treatment caused 53% and 61% inhibitions in tumor growth and prostatic weight respectively. The present data show that the inhibitory effects of flutamide and finasteride on Shionogi tumor and prostate growth are nearly additive or additive respectively, and suggest that such a combination of the two compounds could provide the basis for further improvement of the endocrine therapy of prostate cancer and induce the maximal degree of apoptosis or cancer cell death. The limited efficacy of the 5α-reductase inhibitor alone resulting from the increased intratumoral testosterone concentrations can be regained by the antiandrogen, thus permitting complementary action of the two compounds. The present data also show that the maximal inhibitory effects are achieved with the triple combination of castration, a pure antiandrogen, and a 5α-reductase inhibitor.

Endocrine-Related Cancer (1996) 3 217-227

Prostatic carcinogenesis is associated with changes in the androgen receptor (AR) axis converting it from a paracrine dependence upon stromal signaling to an autocrine-initiated signaling for proliferation and survival of prostatic cancer cells. This malignant conversion is due to gain of function changes in which the AR activates novel genomic (i.e. transcriptional) and non-genomic signaling pathways, which are not present in normal prostate epithelial cells. During further progression, additional molecular changes occur which allow these unique malignancy-dependent AR signaling pathways to be activated even in the low androgen ligand environment present following androgen ablation therapy. These signaling pathways are the result of partnering the AR with a series of other genomic (e.g. transcriptional co-activators) or non-genomic (e.g. steroid receptor co-activator (Src) kinase) signaling molecules. Thus, a combinatorial androgen receptor targeted therapy (termed CART therapy) inhibiting several points in the AR signaling cascade is needed to prevent the approximately 30,000 US males per year dying subsequent to failure of standard androgen ablation therapy. To develop such CART therapy, a series of agents targeted at specific points in the AR cascade should be used in combination with standard androgen ablative therapy to define the fewest number of agents needed to produce the maximal therapeutic anti-prostate cancer effect. As an initial approach for developing such CART therapy, a variety of new agents could be combined with luteinizing hormone-releasing hormone analogs. These include: (1) 5α-reductase inhibitors to inhibit the conversion of testosterone to the more potent androgen, dihydrotestosterone; (2) geldanamycin analogs to downregulate AR protein in prostate cancer cells, (3) ‘bulky’ steroid analogs, which can bind to AR and prevent its partnering with other co-activators/signaling molecules, and (4) small molecule kinase inhibitors to inhibit MEK, which is activated as part of the malignant AR signaling cascade.

Abstract

After 3 h of incubation at room temperature, hydroxyFlutamide, the active metabolite of Flutamide (Eulexin), and Casodex (bicalutamide), an analog of Flutamide, have comparable potency to displace [³H]R1881 from the human prostate and rat ventral prostate androgen receptors contrary to the previous claims that Casodex was four times more potent using different incubation conditions. Binding data, in fact, must be interpreted with caution, since they are very much dependent upon the duration and temperature of incubation. In the more appropriate intact cell situation, hydroxyFlutamide is approximately three times more potent than Casodex at inhibiting dihydrotestosterone-stimulated proliferation of androgen-sensitive mouse Shionogi carcinoma cells in vitro. Under in vivo conditions, in the orchiectomized rat supplemented with androstenedione implants, Flutamide is about three times more potent than Casodex at inhibiting ventral prostate and seminal vesicle weight. When both compounds were administered for 7 days to intact rats, Flutamide and Casodex showed similar apparent potency. However, taking into account the much higher plasma levels of testosterone and dihydrotestosterone in intact animals treated with Flutamide compared with those treated with Casodex, the estimated potency of Flutamide in the intact rat is also at least three times higher than that of Casodex. The present data, contrary to previous claims based upon the inappropriate intact rat model clearly show that Flutamide is at least three times more potent than Casodex in rat and mouse tissues. These data are opposite to those obtained in the inappropriate intact rat model where Casodex was reported to be five to ten times more potent than Flutamide. Using more appropriate models of androgen action, the present data thus indicate a 15- to 30-fold lower estimate of the potency of Casodex. Since the choice of the dose of Casodex to be used for the treatment of prostate cancer patients is based upon such a large overestimate of the true potency of Casodex, the present data should help the choice of a more appropriate dose of this antiandrogen for the treatment of prostate cancer.

Endocrine-Related Cancer (1996) 3 229-241

Prospective data are lacking on early somatostatin analog (SSA) therapy in bronchopulmonary neuroendocrine tumors (BP-NETs; typical carcinoids and atypical carcinoids (TCs and ACs)). SPINET (EudraCT: 2015-004992-62; NCT02683941) was a phase III, double-blind study of lanreotide autogel/depot (LAN; 120 mg every 28 days) plus best supportive care (BSC) vs placebo plus BSC, with an optional open-label treatment phase (LAN plus BSC). Patients had metastatic/unresectable, somatostatin receptor (SSTR)-positive TCs or ACs. Recruitment was stopped early owing to slow accrual; eligible patients from the double-blind phase transitioned to open-label LAN. The adapted primary endpoint was progression-free survival (PFS) during either phase for patients receiving LAN. Seventy-seven patients were randomized (LAN, n = 51 (TCs, n = 29; ACs, n = 22); placebo, n = 26 (TCs, n = 16; ACs, n = 10)). Median (95% CI) PFS during double-blind and open-label phases in patients receiving LAN was 16.6 (11.3; 21.9) months overall (primary endpoint), 21.9 (12.8, not calculable (NC)) months in TCs, and 13.8 (5.4; 16.6) months in ACs. During double-blind treatment, median (95% CI) PFS was 16.6 (11.3; 21.9) months for LAN vs 13.6 (8.3; NC) months for placebo (not significant); corresponding values were 21.9 (13.8; NC) and 13.9 (13.4; NC) months, respectively, in TCs and 13.8 (5.4; 16.6) and 11.0 (2.8; 16.9) months, respectively, in ACs. Patients’ quality of life did not deteriorate and LAN was well tolerated. Although recruitment stopped early and the predefined sample size was not met, SPINET is the largest prospective study to date of SSA therapy in SSTR-positive TCs and ACs and suggests clinical benefit in TCs.