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Effective Delivery of Anti-cancer Agent to Brain

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  2. Effective Delivery of Anti-cancer Agent to Brain
  3. Antibody Against EGFR Causes Leukocyte Infiltration of Tumor
  4. Green Tea and Exercise Can Change Your DNA
  5. Local Delivery of Chemotherapy in Peritoneal Carcinomatosis

Kuroda et al., pp. 2505–2511

Malignant glioma is an aggressive disease with a mean survival rate of less than 1 year. Previous experimental treatment using CPT-11, a prodrug of the plant alkaloid SN-38, showed low response rates. CPT-11 in combination with VEGF monoclonal antibody, however, led to a 6-month overall survival rate of 77%. The downside of this treatment is its associated adverse effects.

For this reason Kuroda et al., investigated whether the delivery of SN-38 in a micelle could result in selective delivery with increased efficacy and reduced toxicity. NK102, a SN-38 incorporating micelle, was observed by the authors to be over 400 times more potent than CPT-11 in inhibiting growth of glioma cell lines.

Glioma cells were then injected into the cerebral hemisphere of athymic nude mice. In mice that received NK012, the tumor concentration of free SN-38 was maintained after injection at a far greater concentration and longer time period—up to 72 hours—than after injection of CPT-11. Most significantly the NK012-treated mice showed much improved survival rates compared to the CPT-11 treated groups (p = 0.0014).

This study shows that NK012 is a very promising substitute for using CPT-11/VEGF in patients with malignant glioma and warrants further clinical trials.

Antibody Against EGFR Causes Leukocyte Infiltration of Tumor

  1. Top of page
  2. Effective Delivery of Anti-cancer Agent to Brain
  3. Antibody Against EGFR Causes Leukocyte Infiltration of Tumor
  4. Green Tea and Exercise Can Change Your DNA
  5. Local Delivery of Chemotherapy in Peritoneal Carcinomatosis

Hoffmann et al., pp. 2589–2596 Masago et al., pp. 2744–2749

Overexpression of epidermal growth factor receptor (EGFR) is characteristic of squamous cell carcinoma of the head and neck (SCCHN). Monoclonal antibodies (mAbs) against the external domain of EGFR are used as anti-tumor therapy although their mechanism is not fully understood.

In this paper, the authors examine the effects of anti- EGFR mAb in a 3-dimensional spheroid model containing SCCHN tumor cells expressing EGFR. Co-incubation of tumor spheroids with allogenic PMBCs led to minor PMB infiltration into the spheroids. This effect was greatly enhanced in cells treated with anti-EGFR mAb and positively correlated (r = 0.9, p < 0.05) with tumors in which EGFR expression was highest.

EGFR signaling appears to be involved in the infiltration process as a Fab fragment of anti-EGFR and an EGFR tyrosine kinase inhibitor induced PBMC infiltration. A cytokine array analysis revealed that MCP-1, a cytokine important in migration, was overexpressed. Treatment of tumor monolayers in a transwell experiment with neutralizing anti-MCP-1 could significantly inhibit the migratory effect that anti-EGFR mAb has on PBMCs.

This report clearly demonstrates a mechanism whereby the action of anti-EGFR recruits leukocytes into tumors and may explain some of the anti-tumoral effects of this mAb.

On pages 2744–2749 Masago and colleagues also examine EGFR activation but in this case in papillary thyroid cancer. Initially identified in a case study, they found that mutations in the EGFR tyrosine kinase domain were relatively common in about 30% patients with papillary thyroid cancer and conclude that EGFR tyrosine kinase inhibitors may be useful in treating these patients.

Green Tea and Exercise Can Change Your DNA

  1. Top of page
  2. Effective Delivery of Anti-cancer Agent to Brain
  3. Antibody Against EGFR Causes Leukocyte Infiltration of Tumor
  4. Green Tea and Exercise Can Change Your DNA
  5. Local Delivery of Chemotherapy in Peritoneal Carcinomatosis

Yuasa et al., pp. 2677–2682

DNA methylation is a common epigenetic change found in cancer. Studies with monozygotic twins suggest that environmental factors can cause epigenetic changes.

Previously the authors had shown that CDX2 methylation negatively correlated with green tea intake. In this study they expand their investigation to 6 genes whose promoters are commonly methylated in gastric cancer (CDX2, BMP-2, p16, CACNA2D3, GATA-5 and ER) and look at several dietary and lifestyle factors.

The methylation frequencies of the 6 genes in 106 gastric cancers varies from 9 to 59%. Methylation frequencies of CDX2 and BMP-2 were found to be lower in patients who consumed more than 7 cups of green tea/day than in patients who drank 6 cups or less: 8% versus 27.5% (p = 0.04) and 4% versus 27.5 % (p = 0.02), respectively. CACNA2D3 methylation was found more frequently in patients with no physical activity than in those who had 1 hour or more of physical activity each week −44% versus 24% (p = 0.03).

It is not clear how the components of green tea or physical activity could affect DNA methylation but this warrants further study. This report highlights lifestyle factors which have previously emerged through epidemiological studies and may have impact on the methylation status of tumor-related genes.

Local Delivery of Chemotherapy in Peritoneal Carcinomatosis

  1. Top of page
  2. Effective Delivery of Anti-cancer Agent to Brain
  3. Antibody Against EGFR Causes Leukocyte Infiltration of Tumor
  4. Green Tea and Exercise Can Change Your DNA
  5. Local Delivery of Chemotherapy in Peritoneal Carcinomatosis

Keese et al., pp. 2701–2708

Colorectal cancer patients who develop peritoneal carcinomatosis (PC) face a disease with increased morbidity and mortality. Chemotherapeutic agents used to treat PC are associated with multiple side effects.

For this reason, Keese et al., tested local delivery of the chemotherapeutic agents doxorubicin, mitoxantrone and irinotecan using a drug-eluting bead (DEB) system. In vitro testing of doxorubicin, mitoxantrone and irinotecan on murine colon carcinoma cells showed that both free and DEB could induce apoptosis, the free drug often giving a better response. In vivo, however, DEB treatment was found to be much more effective and better tolerated. Experimental PC was induced in mice and single or multiple injections of doxorubicin or mitoxantrone in free or DEB form were compared. Free drug administration was most effective as a single dose but otherwise was associated with high mortality. Tumor load and volume were decreased most in mice receiving three injections of doxorubicin DEB.

This study demonstrates that DEB may be a means of delivering high doses of chemotherapeutic drugs in the peritoneal cavity without excess adverse effects.