Role of CA19.9 in predicting bevacizumab efficacy for metastatic colorectal cancer patients.

CEA and CA19.9 are biomarkers routinely measured for monitoring treatment response in metastatic colorectal cancer (MCRC) patients, yet their predictive value during therapies containing new antineoplastic drugs (i.e. FOLFIRI/OLFOX/Bevacizumab) has not yet been investigated. Consecutive chemotherapy-naive MCRC patients treated with either standard chemotherapy-alone (FOLFIRI/FOLFOX) or chemotherapy+bevacizumab (FOLFIRI+bevacizumab) were included in the analysis. Patients had to have serial biweekly measurement of CEA and CA19.9 available for at least three months of treatment. Primary study endpoint was Progression Free Survival (PFS). Biomarker levels and type of treatment as well as major demographic and clinical factors were analyzed for their impact on PFS. Out of 243 evaluated MCRC patients, 87 had biomarkers available as per inclusion criteria. Among all evaluated factors only type of treatment (chemotherapy-alone vs chemotherapy+bevacizumab) and baseline CA19.9 (> vs < normal) were independently associated with PFS, whilst neither baseline CEA nor biomarker reduction during therapy reached statistical significance. When patients with different baseline CA19.9 levels were analysed separately, only patients with abnormal CA19.9 benefited significantly from the administration of bevacizumab.The current study demonstrated a significant predictive value of CA19.9, but not of CEA and biomarker reduction, for MCRC patients treated with new antineoplastic drugs. Moreover, only patients with abnormal baseline CA19.9 levels benefited significantly from bevacizumab.

Optimal dose of stereotactic radiosurgery for acoustic neuromas: A systematic review.

Radiosurgery is increasingly employed in the treatment of acoustic neuroma, but the optimal dose in terms of long-term tumour control and minimal adverse effects has not been established. We performed a systematic review of the published literature of radiosurgery of acoustic neuroma to assess whether the use of low dose radiosurgery is as effective as high dose treatment. Reports of radiosurgery for acoustic neuroma were identified through a Medline search. Studies with at least 15 patients and a median follow-up longer than 12 months were included. The relationship between actuarial 5-year progression-free survival (PFS), and tumour and treatment parameters was examined. Forty-two studies were included. Tumour control following lower radiosurgery doses was similar to that reported following high doses. Only 12 studies reported actuarial outcomes at 5 years. There was no relationship between PFS at 5 years and dose to the tumour margin. Radiosurgery of larger tumours was associated with lower 5 year PFS (p < 0.05). Although on initial inspection radiosurgery of acoustic neuroma with doses of 12 - 13 Gy seems to be as effective as higher dose treatment, the available reports are subject to a number of confounding factors, are not sufficiently statistically powered and there is only limited long-term actuarial outcome data. Currently, available studies do not provide sufficient confidence to support the claim that low dose radiosurgery is equally effective as higher doses in the long-term control of acoustic neuroma.

Poly (ADP-ribose) polymerase inhibitor increases apoptosis and reduces necrosis induced by a DNA minor groove binding methyl sulfonate ester.

The poly(ADP-ribose) polymerase (PARP) is involved in cell recovery from DNA damage, such as methylation of N3-adenine, that activates the base excision repair process. In the present study we demonstrated that MeOSO(2)(CH(2))(2)-lexitropsin (Me-Lex), a methylating agent that almost exclusively produces N3-methyladenine, induced different modalities of cell death in human leukemic cell lines, depending on the presence of PARP inhibitor. Growth inhibition, provoked by the combination of Me-Lex and PARP inhibitor, was associated with a marked down-regulation of c-myc, increased generation of single strand breaks and apoptosis. When used as single agent, at concentrations that saturated cell repair ability, Me-Lex induced mainly cell death by necrosis. Surprisingly, addition of a PARP inhibitor enhanced apoptosis and reduced the early appearance of necrosis. Telomerase activity was completely suppressed in cells exposed to Me-Lex alone, by 24 h after treatment, whereas it did not change when Me-Lex was combined with PARP inhibitor. Thereafter, inhibition of telomerase was observed with both treatments. The results suggest new insights on different modalities of cell death induced by high levels of N3-methyladenine per se, or by the methylated base in the presence of PARP inhibitor.

Combined effects of adenovirus-mediated wild-type p53 transduction, temozolomide and poly (ADP-ribose) polymerase inhibitor in mismatch repair deficient and non-proliferating tumor cells.

Lack of p53 or mismatch repair (MR) function and scarce cell proliferation are commonly associated with tumor cell resistance to antineoplastic agents. Recently, inhibition of poly(ADP-ribose) polymerase (PARP) has been considered as a tool to overcome resistance of MR-deficient tumors to methylating agents. In the present study we demonstrated that infection with p53 expressing adenovirus (Ad-p53), enhances chemosensitivity of MR-deficient tumor cell lines to the methylating agent temozolomide (TZM), either used as single agent or, more efficiently, when combined with PARP inhibitor. Moreover, the association of Ad-p53 with drug treatment induced a more pronounced growth inhibitory effect than that provoked by Ad-p53 infection only. Cells, growth arrested by p53 transduction, and then subsequently exposed to the drugs, were still highly susceptible to cytotoxicity induced by TZM and PARP inhibitor. The results suggested that this drug combination might be effective even in non-proliferating tumor cells. It is conceivable to envisage future possible strategies to enhance cytostatic or cytotoxic effects induced by Ad-p53, based on the use of TZM, alone or combined with PARP inhibitor for the therapy of resistant tumors.

Effects of single or split exposure of leukemic cells to temozolomide, combined with poly(ADP-ribose) polymerase inhibitors on cell growth, chromosomal aberrations and base excision repair components.

PURPOSE: To evaluate the antitumor activity of single versus split exposure of neoplastic cells to temozolomide (TZM) and poly(ADP-ribose) polymerase (PARP) inhibitor. METHODS: A leukemic Jurkat cell line and freshly isolated leukemic blasts were used. Jurkat cells are resistant to O6-methylguanine damage induced by TZM due to high levels of O6-alkylguanine-DNA alkyltransferase and to a functional defect in the mismatch repair system. Cells were treated with 3-aminobenzamide or with NU1025 to inhibit PARP activity. TZM was added to cell cultures immediately after PARP inhibitors. The concentrations of TZM used were 62.5 microM (corresponding to the peak plasma concentration in patients) or 125 microM. TREATMENT DESIGN: Cells were treated with 125 microM TZM plus PARP inhibitors (single exposure), or twice with 62.5 microM TZM plus PARP inhibitors with an interval of 24 h between treatments (split exposure). Tumor cell growth, clastogenicity and base excision repair gene transcripts or enzymatic activity were evaluated. RESULTS: The split exposure of Jurkat cells to TZM induced more pronounced and persistent growth inhibition and comparable chromosome damage in comparison with the single exposure. In addition, PARP inhibitors potentiated the cytotoxic effects induced by repeated treatment with TZM in fresh leukemic blasts. A marked decrease in X-ray repair cross-complementing 1 transcript and methylpurine glycosylase (MPG) transcript was detected in Jurkat cells subjected to the split exposure. In this case, a significant reduction in the corresponding enzymatic activity was also observed. CONCLUSIONS: Cytotoxicity induced by TZM and PARP inhibitors can be improved by a fractionated modality of drug treatment. The reduction in MPG transcript and function would presumably contribute to an increase in cell susceptibility to DNA damage induced by the methylating agent and PARP inhibitors.

Cytotoxic and clastogenic effects of a DNA minor groove binding methyl sulfonate ester in mismatch repair deficient leukemic cells.

Mismatch repair deficiency contributes to tumor cell resistance to O6-guanine methylating compounds and to other antineoplastic agents. Here we demonstrate that MeOSO2(CH2)2-lexitropsin (Me-Lex), a DNA minor groove alkylating compound which generates mainly N3-methyladenine, has cytotoxic and clastogenic effects in mismatch repair-deficient leukemic cells. Moreover, MT-1 cells, which express p53 upon drug treatment and possess low levels of 3-methylpurine DNA glycosylase activity, are more susceptible to cytotoxicity induced by Me-Lex, with respect to p53-null and 3-methylpurine DNA glycosylase-proficient Jurkat cells. In both cell lines, the poly(ADP-ribose) polymerase inhibitor 3-aminobenzamide, which inhibits base excision repair capable of removing N-methylpurines, increases cytotoxicity and clastogenicity induced by Me-Lex or by temozolomide, which generates low levels of N3-methyl adducts. The enhancing effect is more evident at low Me-Lex concentrations, which induce a level of DNA damage that presumably does not saturate the repair ability of the cells. Nuclear fragmentation induced by Me-Lex + 3-aminobenzamide occurs earlier than in cells treated with the single agent. Treatment with Me-Lex and 3-aminobenzamide results in augmented expression of p53 protein and of the X-ray repair cross-complementing 1 transcript (a component of base excision repair). These results indicate that N3-methyladenine inducing agents, alone or combined with poly(ADP-ribose) polymerase inhibitors, could open up novel chemotherapeutic strategies to overcome drug resistance in mismatch repair-deficient leukemic cells.