Cancer Res Treat.  2009 Jun;41(2):80-86.

Modest Anti-Cancer Activity of a Bile Acid Acylated Heparin Derivative in a PC14PE6 Induced Orthotopic Lung Cancer Model

• Cui ZY
• Park MJ
• Lee J
• Ahn JS
• Ahn MJ
• Seo SW
• Park JW
• Byun Y
• Park K

Abstract

PURPOSE
A novel chemically modified heparin derivative, heparin-deoxycholic acid nano-particles, has lower anticoagulant activity, and was recently reported to have significant anti-tumor effects on squamous head and neck cancer cells. Therefore, the aim of this study was to evaluate the anti-tumor effects of heparin-deoxycholic acid nano-particles in a human lung adenocarcinoma cell line. MATERIALS AND METHODS: An orthotopic lung cancer model in 16 mice was developed using intra-thoracic injections of 0.5x10(6) PC14PE6 cells. Ten days after inoculation, the mice were divided into two groups. PBS and Heparin-DOCA particles were injected once a day every 3 days in the tail vein, for a total of 5 injections. The body weight and survival of each mouse were monitored and the tumor size in the lung was measured by SPECT-CT before and after heparin-DOCA nano-particle treatment. RESULTS: IThe HD particles had no significant cytotoxicity when the PC9 cells were treated in vitro. There was no statistical difference in tumor size, body weight and survival between the HD treated and control groups in vivo. Furthermore, there was no difference in the amount of CD31 between tumor tissues in the two study groups. CONCLUSION: HD synthesized with unfractionated heparin had no apparent inhibitory effects on tumor growth in a PC14PE6 cell induced orthotopic lung cancer mouse model. The HD particles did not significantly inhibit tumor-induced angiogenesis at the tumor sites.

Keyword

Lung; Adenocarcinoma; Mouse; Heparin; Derivatives; Angiogenesis

MeSH Terms

Adenocarcinoma
Animals
Bile
Body Size
Body Weight
Cell Line
Head and Neck Neoplasms
Heparin
Humans
Lung
Lung Neoplasms
Mice
Veins
Adenocarcinoma
Heparin
Lung Neoplasms

Figure

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  Fig. 1 Size distribution of the HD particles. The HD particle solution shows a uniform size distribution of about 89±2.2 nm after filtering through a 0.45 µm pore size syringe filter; (A) before filtration; (B) after filtration.

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  Fig. 2 SPECT-CT images of orthotopic lung cancer. 3 Dimensional images were generated by SPECT-CT scanning. The length of the transverse plane=a was marked as x, and indicated the length of the tumor mass from the left to right side; the length of the coronal plane=b was marked as y, and indicated the length of the tumor mass up and down; the length of the sagittal plane=c was marked as z, and indicated the length of the tumor mass from front to back. The volume of the tumor in the mouse lung was calculated according to the formula V=πabc/6.

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  Fig. 3 Cytotoxicity of HD particles. Cell viability assay of HD particles compared with the same dose of heparin in the PC9 cells. There was no significant difference between the heparin and HD particle treated groups. (△) Heparin treated group (■) HD particle treated group.

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  Fig. 4 Effects of HD particles on body weight and tumor volume. The mean body weight of the two groups was not significantly changed during the study; the control and HD treated groups were not significantly different (A). The mean size of the tumor volume at three intervals in the HD particle treated group was similar to the control group (B); the difference between the groups was not statistically significant (p>0.05).

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  Fig. 5 Survival rates for control and HD particle treated mice. Survival rates did not significantly differ between the control and HD particle treated group with regard to the mean number of days of survival after tumor inoculation (p=0.943>0.05).

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  Fig. 6 Microscopic features of the tumor in the lungs of the mice. The tumor mass from the PBS treated animals (A) and HD particle treated animals (B) were immunostained using rat anti mouse CD31 monoclonal antibodies (magnification: ×200).

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