Enzalutamide for the treatment of castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) remains a major clinical challenge, given the mechanistic heterogeneity due to a complex signal transduction network. Enzalutamide (MDV-3100), recently approved by the U.S. Food and Drug Administration (FDA) at a dose of 160 mg/day for the treatment of CRPC, blocks androgen signaling by directly binding to the androgen receptor (AR) and inhibiting nuclear translocation and coactivator recruitment of the ligand-receptor complex. In preclinical studies, enzalutamide has been shown to block the binding of AR to DNA, resulting in apoptosis and retardation of tumor growth. Clinically, a phase I/II study (N = 140) revealed that enzalutamide had an optimal safety profile and significant antitumor activity in patients with CRPC regardless of prior chemotherapy. In the AFFIRM phase III trial (N = 1,199), oral enzalutamide significantly improved survival in men with metastatic CRPC after chemotherapy. Currently, a phase III trial (PREVAIL) is under way to determine the effectiveness of enzalutamide in patients who have not received prior docetaxel chemotherapy.

A phase I trial of weekly paclitaxel, 13- cis-retinoic acid, and interferon alpha in patients with prostate cancer and other advanced malignancies.

PURPOSE: Based on prior studies demonstrating the effect of 13- cis-retinoic acid and interferon alpha (CRA/IFN) in decreasing the expression of the antiapoptotic protein bcl-2, our prior clinical study of CRA/IFN with paclitaxel (TAX) administered every 3 weeks, and data demonstrating increased activity of weekly TAX against prostate cancer, we designed a phase I study of weekly TAX in combination with CRA/IFN in patients with prostate cancer and other advanced malignancies. To develop a marker of drug effect, we assessed bcl-2 downregulation in patient peripheral blood mononuclear cells (PBMC). METHODS: Enrolled in the study were 14 patients with prostate cancer or other advanced malignancies, and 13 were treated with 1 mg/kg CRA on days 1 and 2, 6 MU/m(2) IFN subcutaneously on days 1 and 2, and TAX at increasing doses on day 2 each week for 6 weeks out of an 8-week cycle. The effect of CRA/IFN on bcl-2 expression was assessed in PBMCs by immunoblotting. RESULTS: The combination of CRA/IFN and TAX was well tolerated. Dose-limiting toxicities (DLT) in the first cycle of therapy included one patient with fever and neutropenia, and one patient with grade 4 hypertriglyceridemia. The recommended phase II dose of TAX in this combination was 80 mg/m(2). Of 13 patients assessable by tumor markers or scans, 5 had stable disease and 2 had a biochemical partial response including a patient with a decrease in PSA of >50% while on study. The assessment of patient PBMC bcl-2 was feasible in ten patients. CONCLUSIONS: This is the first study in which the safety and clinical activity of weekly TAX combined with CRA/IFN has been demonstrated. The assessment of PBMC bcl-2 is feasible in this weekly chemotherapy schedule

Mitoxantrone in patients with prostate specific antigen progression after local therapy for prostate carcinoma.

BACKGROUND: Molecular mechanisms of chemotherapy resistance are present in prostate carcinoma, some of which increase after androgen ablation (AA) therapy. Therefore, the authors hypothesized that chemotherapy in patients with prostate specific antigen (PSA) progression after local therapy, before androgen ablation therapy, will have greater antitumor activity. METHODS: Twenty-three hormone-naive patients with PSA progression after prostatectomy or radiation therapy were registered in this study. Twenty-two were treated with 10 mg/m(2) of mitoxantrone initially, followed by 12 mg/m(2) every 3 weeks for a maximum of 8 cycles. Prostatectomy specimens were assessed, when possible, for topoisomerase II alpha, multidrug resistance protein MRP, and bcl-2 by immunohistochemistry. RESULTS: Twenty-two patients received a total of 131 cycles of therapy. Three patients had transient Grade 3 or 4 neutropenia without fever. During treatment, 10 of 22 patients showed a decrease in PSA, without an associated decrease in testosterone. In this group of 10 patients, the mean PSA decrease was 29% at 3 months and 43% at 6 months. Overall, 4 of 22 patients had a decrease in PSA of greater than or equal to 50%. The PSA decreased in three of seven patients whose cancer overexpressed MRP and in three of seven patients who overexpressed bcl-2. No patient with overexpression of topoisomerase II alpha (n = 4) had a decrease in PSA during the study. CONCLUSIONS: To the authors' knowledge, this is the first reported study of mitoxantrone in patients with hormone-naive prostate carcinoma and PSA progression after local therapy; mitoxantrone was safe and biochemically active, similar to prior studies in hormone refractory prostate carcinoma, suggesting that critical molecular mechanisms of chemotherapy resistance are present independent of AA. Further studies are warranted to determine whether pharmacogenomic assessment of topoisomerase II, MRP, or bcl-2 may predict for response to mitoxantrone.

Prevention and management of colorectal cancer in women.

OBJECTIVE: To review prevention and management strategies for colorectal cancer, with an emphasis on studies pertaining to women. DATA SOURCES: Articles published from January 1990 through February 2001 identified through a MEDLINE search using the term colorectal cancer and the additional terms screening, prevention, and treatment. Additional references were identified from the bibliographies of the retrieved articles. DATA SYNTHESIS: Colorectal cancer is the third most common non-skin cancer in women, after breast and lung cancers. Many women underestimate their risk of colorectal cancer, which may lead them to underuse screening measures that have been proven to reduce disease morbidity and mortality. For average-risk women and men > or = 50 years of age, pharmacists should recommend regular screening for early detection and prevention of colorectal cancer. In its earliest, most curable stages, colorectal cancer is often asymptomatic. However, patients who report signs and symptoms, such as blood in the stool, abdominal pain, changes in bowel habits, unexplained weight loss, or iron deficiency anemia, should be referred for medical evaluation. The use of chemopreventive agents for colorectal cancer, such as nonsteroidal anti-inflammatory drugs, hormone replacement therapy, and dietary calcium, holds significant promise, but further studies are needed before these agents can be recommended for cancer prevention in the general population. Surgical resection is the primary treatment modality for colorectal cancer, and adjuvant chemotherapy is recommended in patients with stage III disease and some high-risk patients with stage II disease. Pharmacists should be aware that women are more susceptible to dose-related toxicity effects of fluorouracil and leucovorin combination chemotherapy, the first-line regimen for adjuvant chemotherapy. CONCLUSION: Although often perceived as a disease that primarily affects men, colorectal cancer is an equally important health concern for women. By providing education and counseling, pharmacists can help raise women's awareness of this disease and encourage them to take steps to significantly reduce their risk.

Phase I clinical and pharmacologic study of 13-cis-retinoic acid, interferon alfa, and paclitaxel in patients with prostate cancer and other advanced malignancies.

PURPOSE: Recent studies demonstrate that retinoids decrease expression of the anti-apoptotic protein bcl-2, enhance the effect of chemotherapy, and act synergistically with interferon alfa (IFNalpha) to inhibit tumor cell growth in vitro. A phase I trial of 13-cis-retinoic acid (CRA), IFNalpha, and paclitaxel (TAX) was conducted to determine the toxicity and recommended phase II dose of this combination. Pharmacodynamic studies were performed to determine whether CRA and IFNalpha could modulate bcl-2 expression in vitro and in patients. PATIENTS AND METHODS: Twenty-two patients with prostate cancer or other advanced malignancies were treated with CRA/IFNalpha and escalating doses of TAX. The effect of CRA/IFNalpha on TAX pharmacokinetics was analyzed in both patients and human liver microsomes. The effect of CRA/IFNalpha on bcl-2 expression was assessed in vitro and in peripheral-blood mononuclear cells (PBMCs) by immunoblotting. RESULTS: CRA 1 mg/kg on days 1 to 4, IFNalpha 6 MU/m(2) subcutaneously on days 1 to 4, and TAX 175 mg/m(2) on day 3 was well tolerated. Pharmacokinetic studies demonstrated that CRA/IFNalpha caused a 33% decrease in TAX clearance and a 23% decrease in the area under the concentration-time curve values of the TAX metabolite 6-alfa-hydroxytaxol (6-HT). CRA alone reduced conversion of TAX to 6-HT by 41% in human liver microsomes. CRA/IFNalpha decreased bcl-2 expression in vitro and in PBMCs. CONCLUSION: CRA/IFNalpha and TAX is a well-tolerated regimen. CRA/IFNalpha increases TAX area under the concentration-time curve through an inhibitory effect of CRA on the metabolism of TAX to 6-HT. CRA/IFNalpha can modulate bcl-2 expression in vitro and demonstrates similar biologic activity in patients. Further studies will determine the activity of CRA/IFNalpha/TAX and validate the assessment of bcl-2 in PBMCs as a marker of tumor response.

In vitro activation of irinotecan to SN-38 by human liver and intestine.

BACKGROUND: Irinotecan (CPT-11) is hydrolyzed by carboxyl esterase to the active metabolite SN-38 and oral irinotecan could undergo intestinal and hepatic activation. MATERNALS AND METHODS: Irinotecan was incubated with S9 fractions of human liver and intestinal tissues and the specific activity was determined based on the formation rate of SN-38. RESULTS: Irinotecan was hydrolyzed to SN-38 by hepatic and intestinal S9 fractions with mean (+/- SD) specific activities (pmoles/min/mg) of: liver (8.57 +/- 10.4, n = 8), duodenum (5.06 +/- 3.7, n = 4), jejunum (6.44 +/- 2.8, n = 5), ileum (4.81 +/- 2.4, n = 5), colon (1.93 +/- 1.5, n = 6) and rectum (0.82, n = 1). When incubated with S9 fractions obtained from tumor tissues, there appeared to be a decrease in SN-38 formation compared to matched normal liver and colon tissues. CONCLUSION: Irinotecan undergoes conversion to its active metabolite in human intestinal S9 fractions and there is variability in the extent of SN-38 formation. The localized intestinal activation of irinotecan to SN-38 may provide a rationale for the development of oral irinotecan for gastrointestinal malignancies but could also cause mucosal damage leading to toxicity.

Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer.

BACKGROUND: Herbal mixtures are popular alternatives to demonstrated therapies. PC-SPES, a commercially available combination of eight herbs, is used as a nonestrogenic treatment for cancer of the prostate. Since other herbal medicines have estrogenic effects in vitro, we tested the estrogenic activity of PC-SPES in yeast and mice and in men with prostate cancer. METHODS: We measured the estrogenic activity of PC-SPES with transcriptional-activation assays in yeast and a biologic assay in mice. We assessed the clinical activity of PC-SPES in eight patients with hormone-sensitive prostate cancer by measuring serum prostate-specific antigen and testosterone concentrations during and after treatment. RESULTS: In complementary yeast assays, a 1:200 dilution of an ethanol extract of PC-SPES had estrogenic activity similar to that of 1 nM estradiol, and in ovariectomized CD-1 mice, the herbal mixture increased uterine weights substantially. In six of six men with prostate cancer, PC-SPES decreased serum testosterone concentrations (P<0.05), and in eight of eight patients it decreased serum concentrations of prostate-specific antigen. All eight patients had breast tenderness and loss of libido, and one had venous thrombosis. High-performance liquid chromatography, gas chromatography, and mass spectrometry showed that PC-SPES contains estrogenic organic compounds that are distinct from diethylstilbestrol, estrone, and estradiol. CONCLUSIONS: PC-SPES has potent estrogenic activity. The use of this unregulated mixture of herbs may confound the results of standard or experimental therapies and may produce clinically significant adverse effects.

Chemotherapy for metastatic melanoma during pregnancy.

Melanoma during pregnancy represents a difficult problem. Although surgery is a definitive therapy for early-stage disease, rapidly progressive metastatic disease in pregnancy requires a series of more difficult decisions. We report the use of combination chemotherapy with tamoxifen, carmustine, dacarbazine, and cisplatin in a patient with metastatic melanoma during the second trimester of pregnancy. The patient received 2 cycles of chemotherapy prior to delivery of a healthy 1520-g baby girl at 30 weeks gestation. Placental pathology, however, revealed malignant melanoma in the intervillous space and melanin pigment granules in villous Hofbauer cells and synctial trophoblasts. This report also reviews the literature, assessing the importance of pregnancy as a prognostic factor, the effects of metastasis on the products of conception, and the use of chemotherapy in pregnancy. We conclude that combination chemotherapy can be administered in the second trimester of pregnancy for the treatment of rapidly progressive melanoma without interfering with the successful maturation and delivery of an infant of 30 weeks gestation.

Effect of 13-cis-retinoic acid and alpha-interferon on transforming growth factor beta1 in patients with rising prostate-specific antigen.

The objective of this study was to test the hypothesis that 13-cis-retinoic acid (CRA) and alpha-interferon (IFN-alpha) have antitumor activity in patients with early recurrence of prostate cancer measured by rising prostate-specific antigen (PSA) after local therapy, and that this activity is associated with the increase of plasma transforming growth factor beta1 (TGF-beta1). Thirty patients with a PSA > 7 ng/ml that increased >0.4 ng/ml/month after initial radiation therapy or a PSA > 2.0 ng/ml after prostatectomy were treated with 1 mg/kg/day of CRA and 3 million units of IFN-alpha administered three times per week. Patients were followed clinically with serum measurements of PSA and assessment of toxicity. Biological activity of CRA and IFN-alpha was assessed by the measurement of plasma TGF-beta1. Twenty-six percent of patients had a partial (50% decrease maintained for 1 month) or minimal (<50% decrease maintained for 1 month) biochemical response of PSA, with a median decrease of 23% (11-55%) at 3 months. Plasma TGF-beta1 levels increased with CRA and IFN-alpha therapy and correlated with a decrease in PSA; patients with a decrease in PSA had a 151% increase in TGF-beta1 compared to 27% in patients without a decrease in PSA (P = 0.04). CRA and IFN-alpha can produce transient reduction or stabilization of PSA. The measurement of plasma TGF-beta1 at 1 month of therapy correlates with changes in PSA and may represent a useful marker for the biological effect of these agents; further analysis in larger numbers of patients and methods to optimize these effects should be explored.

A phase I trial of 5-day continuous infusion cisplatin and interferon alpha.

Combination therapy of cisplatin with interferon alpha (IFN) has been shown in several in vitro as well as in vivo models to be synergistic. In order to decrease toxicity seen with cisplatin, 5-day continuous infusions, in place of bolus administration, have been introduced. This led us to investigate the combination of 5-day continuous infusion cisplatin with repeated IFN dosing in a phase I cisplatin dose escalation study. A group of 17 patients were enrolled in this trial. The maximum tolerated dose (MTD) of cisplatin was 20 mg/m2 per day when combined with 3 x 10(6) units IFN given three times a week. The dose-limiting toxicities seen included thrombocytopenia, leukopenia, and nausea and vomiting. Pharmacokinetic analyses of free (unbound or ultrafilterable) platinum revealed that the decay curve fitted a monoexponential model. Pharmacokinetic parameters of cisplatin were found to correlate with toxicity. Both increases in the maximum concentration of cisplatin achieved (Cpmax) as well as the area-under-the-curve (AUC) for free platinum, correlated with the incidence of nausea and vomiting (both acute and delayed) and hematological toxicities (leukopenia and thrombocytopenia). None of the patients exhibited significant changes in renal function while on this study. The free platinum levels were higher than found in similar studies evaluating comparable cisplatin infusions alone. The enhanced toxicities seen in this trial may be explained by the results of an in vitro study using human plasma spiked with cisplatin and IFN that revealed decreased protein binding of cisplatin by 2.5-3.0-fold. Of the 17 patients treated, two non-small cell lung cancer patients obtained a partial response and one malignant melanoma patient obtained complete resolution of a malignant pleural effusion. Considering the acceptable toxicity seen in this trial, we recommend phase II trials be conducted with continuous infusion cisplatin with IFN in the treatment of non-small cell lung cancer.

17 beta-estradiol glucuronide: an inducer of cholestasis and a physiological substrate for the multidrug resistance transporter.

The multidrug resistance (MDR) gene family has been shown to be highly expressed in several normal tissues including the canalicular membrane of the hepatocyte. We report that a cholestatic estrogen metabolite, 17 beta-estradiol glucuronide (E217G), is a substrate for the MDR transporter, P-glycoprotein. In cytotoxicity studies, the MDR sarcoma cell line Dx5 was 4.7-fold resistant to E217G, and the K562/R7 leukemia MDR cell line was 5.0-fold resistant to E217G relative to their parental cell lines. There was also a 2- to 3-fold accumulation defect of [3H]E217G in the MDR cells relative to their parental cell lines. E217G (100 microM) modulated resistance ot doxorubicin, taxol, vinblastine, and etoposide in the Dx5 cells, completely reversing the 30- to 60-fold resistance observed with these agents. E217G had no effect on the toxicity of these compounds in the parental cell line (MES-SA). In contrast, MDR cells were not resistant to the noncholestatic estrogen metabolite, estriol 3-glucuronide, and this metabolite did not modulate resistance to MDR substrates. ATP-dependent transport of [3H]E217G in rat canalicular membranes was inhibited by several MDR substrates including vinblastine, etoposide, verapamil, cyclosporine, and PSC-833.