Improving Tamoxifen Performance in Inducing Apoptosis and Hepatoprotection by Loading on a Dual Nanomagnetic Targeting System.

BACKGROUND: Although tamoxifen (TMX) belongs to selective estrogen receptor modulators (SERMs) and selectively binds to estrogen receptors, it affects other estrogen-producing tissues due to passive diffusion and non-differentiation of normal and cancerous cells and leads to side effects. METHODS: The problems expressed about tamoxifen (TMX) encouraged us to design a new drug delivery system based on magnetic nanoparticles (MNPs) to simultaneously target two receptors on cancer cells through folic acid (FA) and hyaluronic acid (HA) groups. The mediator of binding of two targeting agents to MNPs is a polymer linker, including dopamine, polyethylene glycol, and terminal amine (DPN). RESULTS: Zeta potential, dynamic light scattering (DLS), and Field emission scanning electron microscopy (FESEM) methods confirmed that MNPs-DPN-HA-FA has a suitable size of ~105 nm and a surface charge of -41 mV, and therefore, it can be a suitable option for carrying TMX and increasing its solubility. The cytotoxic test showed that the highest concentration of MNPs-DPN-HA-FA-TMX decreased cell viability to about 11% after 72 h of exposure compared to the control. While the protective effect of modified MNPs on normal cells was evident, unlike tamoxifen, the survival rate of liver cells, even after 180 min of treatment, was not significantly different from the control group. The protective effect of MNPs was also confirmed by examining the amount of malondialdehyde, and no significant difference was observed in the amount of lipid peroxidation caused by modified MNPs compared to the control. Flow cytometry proved that TMX can induce apoptosis by targeting MNPs. Real-time PCR showed that the modified MNPs activated the intrinsic and extrinsic mitochondrial pathways of apoptosis, so the Bak1/Bclx ratio for MNPs-DPN-HA-FA-TMX and free TMX was 70.82 and 0.38, respectively. Also, the expression of the caspase-3 gene increased 430 times compared to the control. On the other hand, only TNF gene expression, which is responsible for metastasis in some tumors, was decreased by both free TMX and MNPs-DPN-HA-FA-TMX. Finally, molecular docking proved that MNPs-DPN-HA-FA-TMX could provide a very stable interaction with both CD44 and folate receptors, induce apoptosis in cancer cells, and reduce hepatotoxicity. CONCLUSION: All the results showed that MNPs-DPN-HA-FA-TMX can show good affinity to cancer cells using targeting agents and induce apoptosis in metastatic breast ductal carcinoma T-47D cell lines. Also, the protective effects of MNPs on hepatocytes are quite evident, and they can reduce the side effects of TMX.

Pemetrexed-based chemotherapy in advanced lung adenocarcinoma patients with different EGFR genotypes.

Advanced lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) activating mutations usually are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs), but whether EGFR-mutant lung adenocarcinoma is also responsive to pemetrexed-based chemotherapy remains controversial. We conducted a retrospective study to evaluate the efficacy and outcome of pemetrexed-based chemotherapy in advanced lung adenocarcinoma patients with different EGFR mutation statuses. Sixty-nine EGFR-mutant and 89 wild-type patients with advanced lung adenocarcinoma were enrolled. They all had received pemetrexed-based treatments. Chemotherapy objective response rate (ORR), median progression-free survival (mPFS), and thymidylate synthase (TS) expression levels of EGFR-mutant patients were compared with those of EGFR-wild-type patients. For the EGFR-mutant patients treated with first-line platinum/pemetrexed combinations, the ORR was significantly higher than that of the wild-type patients treated with similar regimens (43 vs. 21%, p = 0.039). Nonetheless, for the patients treated with pemetrexed monotherapy, the difference in ORR was not significant between patients with EGFR mutations and those with wild-type EGFR in any line of treatments (in the first-line setting 20 vs. 13%, p = 0.715; in the second-/third-line setting 13 vs. 8%, p = 0.655). On the other hand, the mPFS for the EGFR-mutant patients treated with first-line combinations was also obviously prolonged (8.3 vs. 6.7 months, p = 0.004). However, among the patients receiving second-line platinum/pemetrexed combinations or any line of single-agent pemetrexed, there was no difference in PFS between EGFR-mutant and wild-type patients. Our results indicated that the efficacies and outcomes of pemetrexed treatment in advanced lung adenocarcinoma patients with EGFR activating mutations were similar to those in patients with EGFR-wild-type genotype, except in the setting of first-line platinum/pemetrexed combination chemotherapy.

[Screening for prodromes of chemotherapy-induced vomiting and correlation between prodromes and chemotherapy-induced vomiting in lung cancer patients].

OBJECTIVE: To explore prodromes of chemotherapy-induced vomiting (CIV) and their association with CIV in lung cancer patients. METHODS: The prodromes of CIV in 250 lung cancer patients were analyzed. Logistic regression was used to determine the symptoms most likely correlated with CIV. One hundred fifty-seven patients received medical interventions. The development of correlative symptoms and occurrence of CIV between the intervention and non-intervention groups was analyzed. RESULTS: Among the 250 patients with the prodromes of CIV, the incidence rate of CIV was 67.2%. Logistic regression indicated that nausea, constipation, insomnia, hiccups, anorexia, and history of drinking were correlated with CIV (P < 0.05 for all). Among the 20 symptoms observed in this study, the incidence rates of relatively common symptoms were nausea (72.0%), anorexia (68.4%), taste changes (48.8%), constipation (45.6%), abdominal distension (45.6%), stomach distension(40.4%), and insomnia (40.0%). The incidence rats of all symptoms except hiccups before and after intervention had significant difference (P < 0.05 for all). The incidence rates of CIV were 30.0% in the intervention group and 50.6% in the non-intervention group, with a significant difference between the two groups (P = 0.009). CONCLUSIONS: Prodromes of CIV are closely related to the occurrence of CIV. Timely intervention for prodromes of CIV can reduce the incidence rate of CIV during chemotherapy in lung cancer patients.

[Correlation between baseline plasma D-dimer levels and prognosis in patients with non-smal cell lung cancer].

OBJECTIVE: To investigate the correlation of baseline plasma D-dimer levels and clinicopathological features and tumor VEGF expression in non-small cell lung cancer(NSCLC) patients, and to evaluate the value of D-dimer in predicting survival time. METHODS: A retrospective review of the clinicopathological data of 290 NSCLC patients confirmed pathologically in Tianjin Cancer Hospital from July 2007 to April 2009 was performed. The correlations between plasma baseline D-dimer levels and clinicopathological characteristics and progonosis were analyzed. RESULTS: For 290 NSCLC patients with low ( ≤ 0.3 µg/ml) and high (>0.3 µg/ml) D-dimer levels, the median survival times were 54.0 months and 46.2 months, respectively (P < 0.05), and for the patients with stages I, II, IIIA, IIIB and IV NSCLC, the median survival times were 58.1, 40.6, 26.7 and 23.5 months, respectively (P < 0.05). In the operable patients (stages I, II and IIIa) with low and high D-dimer levels, the median progression-free survivals (PFS) were 35.0 and 11.0 months, respectively (P < 0.05). Furthermore, the median PFSs were 57.2 months and 19.6 months, respectively, in these operable patients without and with lymph node metastasis (P < 0.05). CONCLUSIONS: High levels of baseline plasma D-dimer may indicate advanced disease stage, larger tumor size, lymph node metastasis and stronger tumor angiongenesis to some extent, and may be useful in prediction of survival time in NSCLC patients of different stages.