A pharmacogenetic study of docetaxel and thalidomide in patients with castration-resistant prostate cancer using the DMET genotyping platform.

The anticancer agent docetaxel shows significant inter-individual variation in its pharmacokinetic and toxicity profile. Thalidomide is an active anticancer agent and also shows wide pharmacological variation. Past pharmacogenetic research has not explained this variation. Patients with prostate cancer enrolled in a randomized phase II trial using docetaxel and thalidomide versus docetaxel alone were genotyped using the Affymetrix DMET 1.0 platform, which tests for 1256 genetic variations in 170 drug disposition genes. Genetic polymorphisms were analyzed for associations with clinical response and toxicity. In all, 10 single-nucleotide polymorphisms (SNPs) in three genes were potentially associated with response to therapy: peroxisome proliferator-activated receptor-delta (PPAR-delta), sulfotransferase family, cytosolic, 1C, member 2 (SULT1C2) and carbohydrate (chondroitin 6) sulfotransferase 3 (CHST3). In addition, 11 SNPs in eight genes were associated with toxicities to treatment: spastic paraplegia 7 (pure and complicated autosomal recessive) (SPG7), CHST3, cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6), N-acetyltransferase 2 (arylamine N-acetyltransferase) (NAT2), ATP-binding cassette, sub-family C (CFTR/MRP), member 6 (ABCC6), ATPase, Cu++ transporting, alpha polypeptide (ATP7A), cytochrome P450, family 4, subfamily B, polypeptide 1 (CYP4B1) and solute carrier family 10 (sodium/bile acid cotransporter family), member 2 (SLC10A2). Genotyping results between drug metabolizing enzymes and transporters (DMET) and direct sequencing showed >96% of concordance. These findings highlight the role that non-CYP450 metabolizing enzymes and transporters may have in the pharmacology of docetaxel and thalidomide.

A randomized phase II trial of docetaxel (taxotere) plus thalidomide in androgen-independent prostate cancer.

New therapeutic alternatives are needed to improve outcomes in patients with androgen-independent prostate cancer (AIPC). For several years, researchers at the National Cancer Institute have been interested in elucidating the importance of angiogenesis in the pathogenesis of prostate cancer and in identifying inhibitors of this process. Thalidomide has been shown to inhibit the ability of tumors to recruit new blood vessels. In a recent phase II trial of thalidomide in AIPC, 28% of patients achieved a prostate-specific antigen (PSA) decrease of >40%. The taxane docetaxel also produces PSA and measurable disease responses when used as monotherapy or as a component of combination chemotherapy for AIPC. Thus, based on the single-agent activity of thalidomide and docetaxel, we initiated a randomized phase II study of weekly docetaxel with or without thalidomide, 200 mg at bedtime, in patients with chemotherapy-naive metastatic AIPC. Docetaxel, 30 mg/m(2) intravenously, was administered every 7 days for 3 weeks, followed by a 1-week rest period. Both regimens have been well tolerated among the first 59 treated patients, with a near absence of grade (3/4) myelosuppression. Fatigue, hyperglycemia, and pulmonary toxicity were seen in both groups. Thrombotic events have been seen in the combination arm. Thirty-five percent (6 of 17) of the patients receiving docetaxel alone and 53% (19 of 36) of those receiving docetaxel and thalidomide have had a PSA decrease of at least 50%. Combining a cytotoxic agent with an angiogenesis inhibitor is a promising area of investigation for prostate cancer management.

Renal angiosarcoma: a rare primary genitourinary malignancy.

Sarcomatous lesions of the kidney comprise less than 2% of all primary renal malignancies. Angiosarcomas are an exquisitely infrequent histologic type in this setting and are associated with a universally poor prognosis. We report the eighth known case of primary renal angiosarcoma and review the available literature on this rare entity.

Late extramedullary relapse following bone marrow transplant for AML presenting as acute renal failure and leukemic ascites.

A 22-year-old woman with AML in remission for 3.5 years after BMT relapsed with extramedullary disease presenting as leukemic ascites and recurrent obstructive renal failure. The duration of remission post-transplant and the absence of bone marrow involvement may suggest an improved likelihood of response to further chemotherapy.

Analysis of the active lactone form of 9-aminocamptothecin in plasma using solid-phase extraction and high-performance liquid chromatography.

We have developed a sensitive HPLC assay to quantitate the active lactone form of 9-aminocamptothecin (9AC) in human plasma over the concentration range 10-0.25 nM (0.091 ng/ml). Solid-phase extraction separated 9AC lactone from its less active metabolite, 9AC carboxylate, allowing samples to be stored for up to two months prior to reversed-phase HPLC analysis. An acidic (pH 2.55) isocratic HPLC mobile phase was used to enhance 9AC fluorescence resulting in an over 50-fold increase in assay sensitivity compared to previous methods. This assay was able to measure steady-state 9AC lactone concentrations even at the lowest dose level of 9AC used in our Phase I clinical trial.

Geographic risk factors for viral hepatitis and cytomegalovirus infection among United States Armed Forces blood donors.

In an effort to determine whether residence in a foreign country increases the risk of hepatitis B and C and cytomegalovirus (CMV) infection in United States (US) Armed Forces blood donors, 5719 volunteer donors at four US Navy blood banks were evaluated. Most participants were repeat donors (68%) and were young (mean age, 25 years), male (88%), and white (80%), black (10%), or Hispanic (7%). Birth outside of the United States was reported by 6 percent of subjects, and 34 percent had lived in a foreign country for more than 3 months. Twenty (0.3%) subjects had hepatitis B surface antigen (HBsAg), and 100 (1.7%) had antibody to hepatitis B core antigen (anti-HBc). Thirty-four (0.6%) were repeatably reactive in enzyme-linked immunosorbent assay for antibody to hepatitis C virus (anti-HCV); 11 (0.2%) had anti-HCV in immumoblot assay. Of the 3484 donors tested for anti-CMV, 1117 (32.1%) were positive. When demographic characteristics were controlled for both anti-HBc and anti-CMV seropositivies were independently associated in male blood donors with residence in the Philippines. Geographic factors were not associated with HBsAg and anti-HCV positivity. These findings indicate that the prevalence of serologic markers for viral hepatitis is low in military blood donors, but that residence in the Western Pacific is a risk factor for hepatitis B and CMV infection.