Transformation of alkylating regimen of thiotepa into tepa determines the disease progression through GSTP1 gene polymorphism for metastatic breast cancer patients receiving thiotepa containing salvage chemotherapy.

BACKGROUND: The shifts to second-line chemotherapy for metastatic breast cancer (MBC) were widely required based on pharmaceutical molecular profiles to reach out precision medicine. The emerging precise treatment of cancer requires the implementation of clarified pharmacogenetic profiles which are capable of elucidating the predictive responses to cancer chemotherapy. Therefore we were interested in the analysis of the roles of single nucleotide polymorphism (SNP) of GSTP1 (glutathione S-transferase pi 1 gene) alleles to identify pharmacological links with predictors of clinical responses and toxicities. METHODS: 93 MBC patients receiving thiotepa plus docetaxel chemotherapy were enrolled in this study. Optimized CYP3A5, CYP2B6, and GSTP1 were predominantly selected as candidate genes and their three SNPs (CYP2B6 G516T, CYP3A5 A6986G, and GSTP1 A313G) were genotyped by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF) mass spectrometry. Progression-free survival (PFS), disease control rate, and chemo-related toxicities were recorded. RESULTS: GSTP1 A313G (rs1695) was identified to be related with disease progression. In particular, patients harboring AG/GG genotype demonstrated a statistically longer PFS than those with AA. Multivariate analysis confirmed that AG/GG genotype was associated with both clinical responses and liver-localized metastatic lesions. No correlation was found between these three SNPs and chemotherapy-induced toxicity. CONCLUSIONS: These results suggest that the GSTP1 polymorphism is a novel prognostic marker for clinical response to thiotepa-containing chemotherapy regimens. Such evidence could provide insight into the role of pharmacogenetics to deprive of biases in shifting regimens solely by empirical choices.

Combined-modality treatment of leptomeningeal gliomatosis.

OBJECTIVE: Leptomeningeal gliomatosis (LG) is a clinically uncommon metastatic complication of high-grade gliomas (HGGs), for which there is no consensus regarding treatment. The goal of this study was to determine the toxicity and response rate of combined-modality therapy for the treatment of patients with HGGs and LG. METHODS: Eighteen patients (10 men and 8 women), ranging in age from 28 to 70 years (median, 38 yr), with clinically, neuroradiologically, and cytologically documented LG received intraventricular chemotherapy. Tumor histological types included anaplastic astrocytoma (10 patients) and glioblastoma multiforme (8 patients). Concurrent radiotherapy (11 patients) or systemic chemotherapy (13 patients) was administered as clinically indicated. Methotrexate was administered initially, and treatment was continued for patients in stable or improved condition. For patients who experienced progression, cytosine arabinoside was administered as second-line therapy, followed by N,N',N"-triethylenethiophosphoramide as third-line therapy. Patients underwent bimonthly evaluations with cerebrospinal fluid cytological assessments and neurological examinations. RESULTS: Four to 13 cycles (median, 5 cycles) of intraventricular chemotherapy were administered. Toxicity included aseptic meningitis (12 patients), radiation-induced enteritis (2 patients), and myelosuppression of Grade II or less (4 patients). No patient required hospitalization or transfusions, and no treatment-related deaths occurred. Partial responses were observed for 6 patients, and 12 patients demonstrated progressive disease. The median duration of response was 3 months (range, 2-4 mo). Survival times after the initiation of intraventricular chemotherapy ranged from 2 to 8 months (median, 3.5 mo). The cause of death was progressive LG (14 patients), combined LG and HGG (3 patients), and HGG (1 patient). CONCLUSION: For this small cohort of patients, combined-modality therapy had modest toxicity but minimal palliative efficacy. For the majority of patients with LG, supportive care should be considered.

Pharmacokinetics of thio-TEPA and TEPA in the conventional dose-range and its correlation to myelosuppressive effects.

A total of 13 patients with ovarian cancer were studied during the initial two courses of i.v. thio-TEPA treatment they underwent after primary surgery. Following an increase in the dose from 60 to 80 mg for the second course, no sign of saturation of thio-TEPA elimination processes or of formation of the metabolite TEPA occurred, indicating dose-independent pharmacokinetics. Myelosuppression after courses was registered by serial measurements of platelets and leukocytes. The time to platelet nadir was quite uniformly 3 weeks and tended to be longer than that of leukocytes, which averaged 2 weeks but showed greater interindividual variation. Linear regression analyses of pharmacokinetic parameters versus myelosuppression revealed statistically significant correlations between thio-TEPA pharmacokinetics and the percentage of reductions in leukocytes and platelets at their mean nadirs. In contrast, no such correlation could be demonstrated for TEPA despite its greater exposure to the body in terms of AUC. We advocate further investigation of this pharmacokinetic-pharmacodynamic relationship so as to establish individualized dosing of thio-TEPA.

Thiono compounds. 4. In vitro mutagenic and antineoplastic activity of TEPA and thio-TEPA.

Tris (1-aziridinyl) phosphine oxide (TEPA) and tris (1-aziridinyl) phosphine sulfide (thio-TEPA) induced base pair mutations in the Ames mutagenic assay. Thio-TEPA required metabolic activation while TEPA was active without metabolic activation. Growth of a human vaginal carcinoma (A431), a human breast carcinoma (MDA-MB-231), and a human cervical carcinoma (HeLa) were inhibited in soft agar in vitro at concentrations which induced mutagenesis in the Ames Assay. A fourth line, JEG choriocarcinoma, was sensitive to the antigrowth properties of both drugs at concentrations below that which induced mutagenesis. These data suggest that as more antineoplastic agents become available, and as mean survival times increase, knowledge of the relative in vitro sensitivity of a patient's neoplasm to a specific antineoplastic drug (i.e., dose required for growth inhibition) as a function of its mutagenic index might be useful for prediction of clinical remission, as well as the risk of secondary neoplasm induction.