Antitumor Drugs Modified By Polymers And Their Cytotoxic Activities

A broad-spectrum antineoplastic agents has been found to be effective in combating different types of cancer. However, to achieve complete eradication of tumors, antineoplastic agents are administered systemically in high doses, and almost all drugs effective in killing cancer cells cause damage to other healthy tissues and organs. This is due to the non-specific uptake of these agents by healthy organs such as the kidney, liver, bone marrow, and heart. The adverse side-effects include severe immune suppression, myelosuppression, nephrotoxicity, and cardiotoxicity.Polymer-based antitumor drug loaded implants, pastes and microparticulates provide an opportunity to deliver high, localized doses of drug for a prolonged period directly into a tumor or at the site of tumor resection.In the part of review, it is focus on the macromolecule and small molecule compounds derived from natural products with antitumor activities, and the antitumor activities of polymer derivatives of some small molecule drugs.Liquorice and Angelica are traditional Chinese herbal medicines. Their active components are 180- glycyrrhetic acid (180-GA) and Ferulic acid (FA), which has been reported possessing strong bioactivities in physiology and phamarcology. In this paper, the cytotoxic activities of those drugs were evaluated in vitro by using SRB assay. It was found they have antitumor activities, but not so strong. And the toxicity of GA limited its use in medicine.Polyethylene glycol (PEG) is a polymer which was widely used as a covalent modifier of biological macromolecules and particles as well as a carrier for low molecular weight drugs.Chitooligosaccharide (COS) is the product of the chitosan degradation. It has many interesting biological properties, such as immunological activity, antibacterial activity etc.Because of their advansed physical and chemical properties and pharmapuetical function, PEG, COS and their derivatives have been variously applied in thepharmacyeutical field.To avoid the limitations of these small molecule compounds and to improve the antitumor activities, their derivatives have been synthesized. We used PEG and COS respectively to modify GA and FA. A series of polymer derivatives of GA and FA were synthesized.The PEG and COS derivatives of GA were characterized by element analysis, IR spectra and MS spectra. The SRB assay is now being used in our laboratory for further study of their cytotoxic activities.The GA derivatives modified by PEG(20000) have been found no activities, while the derivatives modified by PEG(600) inhibit the growth of liver tumor BEL-7721 cell and cause death of the cell. They showed stronger cytotoxic activities than GA. (IC₅₀,ga =19.57±1.68 ug/mL, IC_{50, peg(600)-ga}= 4.82±0.15 μg/mL, LC_{50, b-peg(600)-ga}= 26.58±2.6 μg/mL). Furthermore, the derivatives modified by COS have less cytotoxic activities than GA(IC_{50,GA-COS(5:1)}=27.29±0.399μg/mL).FA was modified by PEG and COS, and the derivatives were characterized by element analysis, IR spectra and MS spectra. By using the SRB assay, we found the FA derivatives show stronger cytotoxic activities than FA (IC—(50,fa)= 46.63±7.34μg/mL,IC—(50, PEG(600)-FA)=28.62±1.81μg/mL, IC—(50,B-PEG(600)-FA)=18.74±2.55μg/mL, IC_{50, FA-COS(5:1)}= 38.79±0.85μg/mL).5-Fluorouracil (5-Fu) has been used in the therapy of different solid tumors, such as cancer of the gastrointestinal tract and breast cancer. But its use in clinic is limited by its short plasma half-life, high doses, gastrointestinal toxicity and myelotoxicity.The SRB assay indicated that the inhibition or killing activity of 5-Fu to the SGC-7901 cell, but the PEG (600) derivative of 5-Fu lost the antitumor activity.The data in the present study support some possible mechanism.