Role of the MDM2 promoter polymorphism (-309T>G) in acute myeloid leukemia development.

BACKGROUND: The human homologue of the mouse double minute 2 (MDM2) gene is a negative regulator of Tp53. MDM2-309T>G a functional promoter polymorphism was found to be associated with overexpression thereby attenuation of Tp53 stress response and increased cancer susceptibility. We have planned to evaluate the possible role of MDM2-309T>G polymorphism with risk and response to chemotherapy in AML. MATERIALS AND METHODS: A total of 223 de novo AML cases and 304 age and sex matched healthy controls were genotyped for the MDM2-309T>G polymorphism through the tetra-primer amplification refractory mutation system (ARMS)-PCR method. In order to assess the functional relationship of -309T>G SNP with MDM2 expression level, we quantified MDM2 mRNA in 30 primary AML blood samples through quantitative RT-PCR. Both the (-309T>G) genotypes and the MDM2 expression were correlated with disease free survival (DFS) rates among patients who have achieved complete remission (CR) after first induction chemotherapy. RESULTS: MDM2-309T>G polymorphism was significantly associated with AML development (p<0.0001). The presence of either GG genotype or G allele at MDM2-309 confered 1.79 (95% CI: 1.12-2.86; p<0.001) and 1.46 fold (95%CI: 1.14-1.86; p=0.003) increased AML risk. Survival analysis revealed that CR+ve cases with GG genotype had significantly increased DFS rates (16months, p=0.05) compared to CR+ve TT (11 months) and TG (9 months) genotype groups. Further, MDM2 expression was also found to be significantly elevated in GG genotype patients (p=0.0039) and among CR+ve cases (p=0.0036). CONCLUSIONS: The MDM2-309T>G polymorphism might be involved in AML development and also serve as a good prognostic indicator.

Incidence of Bcr-Abl kinase domain mutations in imatinib refractory chronic myeloid leukemia patients from South India.

Mutations in the Bcr-Abl kinase domain (KD) are a major cause for acquired resistance to imatinib (IM) treatment and have been associated with progression and poor prognosis in chronic myeloid leukemia patients. The present study includes 63 patients resistant to standard imatinib dose of 400 mg according to ELN guidelines. Direct sequencing method is used for mutational analysis. The present study revealed 15 exonic mutations in 46.03 % of patients; among them, seven cases (24.13 %) had multiple mutations. Mutations were found to be higher in sokal high- (45.0 %) and intermediate- (68.42 %) compared to low-risk (29.16 %) group. Mutations were observed in 38.09 % of patients with EUTOS (European Treatment and Outcome Study) high risk and in 50.0 % with low risk. The frequency of mutations was 50.0 % in advanced phase, 47.36 % in late chronic-phase, and 43.33 % in chronic-phase patients. 42.10 % of patients with primary resistance and 52.0 % with secondary resistance had mutations. P-loop and T315I mutations were associated with poor survival in advanced phase patients (85.71 %) (P = 0.03). No significant variation was observed with Bcr-Abl transcript levels between the patients with the presence or absence of mutations (P = 0.73). Bcr-Abl levels were found to be significantly elevated in P-loop and T315I mutation carriers (P = 0.001) and also in T315I mutation-positive patients (P = 0.01). P-loop mutations and T315I are frequent in advanced phases and strongly associated with poor prognosis and survival. Hence, the identification of mutations in IM-resistant CML patients will help in treatment optimization with 2nd- or 3rd-generation tyrosine kinase inhibitors (TKIs).

Safety, tolerability, and pharmacokinetics of a capsule formulation of DRF-1042, a novel camptothecin analog, in refractory cancer patients in a bridging phase I study.

The purpose of this bridging phase I study was to characterize the toxicity, pharmacokinetics, and antitumor effects of a capsule formulation of DRF-1042, a novel camptothecin analog, in refractory solid tumor patients. DRF-1042 was given daily for 5 consecutive days for 2 weeks, repeated every 3 weeks at 81 mg/m(2). Adverse events were monitored following NCI-CTC. Blood samples were processed for bioanalysis using a validated high-performance liquid chromatography method. The pharmacokinetics of lactone and total (lactone + carboxylate) forms was determined on days 1 and 12 using a noncompartmental pharmacokinetic method. Pharmacokinetic data with the capsule formulation were compared with previously reported pharmacokinetic parameters with a suspension formulation. Efficacy was evaluated by applying World Health Organization criteria. Six patients received 10 courses of therapy. Thrombocytopenia and diarrhea were dose-limiting toxicities. The upper limit of the area under the curve of DRF-1042 (lactone and total) with the capsule formulation was higher than a suspension formulation at a similar dose on day 1 (lactone: capsule = 8.53 microMxh, suspension = 5.33 microMxh; total: capsule = 393 microMxh, suspension = 176 microMxh) and day 12 (lactone: capsule = 22.1 microMxh, suspension = 6.1 microMxh; total: capsule = 1302 microMxh, suspension = 309 microMxh). The upper limit of the area under the curve of DRF-1042 (lactone and total) was higher under fed conditions (lactone = 15.9 microMxh, total = 605 microMxh) relative to fasted conditions (lactone = 8.53 microMxh, total = 393 microMxh) on day 1. One patient experienced stable disease. The toxicity and pharmacokinetics of the capsule correlated well with the suspension. The recommended phase II dose is 81 mg/m(2).

Safety, tolerability, pharmacokinetics, and pharmacodynamics of an orally active novel camptothecin analog, DRF-1042, in refractory cancer patients in a phase I dose escalation study.

The objective of this study was to characterize the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and antitumor effects of DRF-1042, a novel camptothecin analog, in refractory solid tumor patients. DRF-1042 was given for 5 consecutive days for 2 weeks, repeated every 3 weeks at 1.5 to 270 mg/m(2). Adverse events were monitored following NCI-CTC. Pharmacokinetics of lactone and total forms were determined using validated high-performance liquid chromatography (HPLC) and noncompartmental methods. Efficacy was evaluated applying World Health Organization (WHO) criteria. The 1st course was used to determine DLT and MTD. Twenty-five patients received 73 courses of therapy. Myelosuppression and diarrhea were DLTs. MTD was 120 mg/m(2)/day. AUC increased approximately linearly with dose. The t(1/2) for lactone and total forms was 9.9 and 29 hours, respectively. AUCs correlated significantly with nadir leucopenia and grade 4 diarrhea. Two complete responses (CRs) and 2 partial responses (PRs) were observed. In addition, 4 stable diseases were observed. The recommended phase II dose is 80 mg/m(2)/day.