Two isolate Chinese hamster cell lines useful in screening for chemotherapeutic drugs targeting the pathways.

Key Words: Cancer research; drug discovery

DESCRIPTION OF THE INVENTION(S): The present invention comprises two Chinese hamster cell lines isolated with our proprietary methodology to achieve complete deficiency in the polyamine biosynthetic pathway and the folate metabolic pathway respectively, and therefore useful in screening for chemotherapeutic drugs targeting the pathways. One cell line unable to transport polyamine has been selected for resistance to methylglyoxal bis guanylhydrazone after mutagenesis with ethylmethane sulphonate. It can be used in screening compounds targeting the polyamine biosynthetic pathway that may or may not use this transport pathway to gain access into the cell and it is also useful to access cytotoxicity and metabolism. The other cell line which is deficient in transporting folates using the reduced folate carrier has been isolated by selection for resistance to methotrexate after mutagenesis with ethane methylsulphonate. It will be useful in screening for drugs targeting the folate metabolic pathway or other metabolic pathways that may or may not use this pathway to gain entry into the cell and it will be also useful as a reporter cell line for assessing the functional consequences of alterations in the reduced folate carrier protein.

BACKGROUND: Polyamines are naturally occurring polycationic alkyl amines that are ubiquitous molecules influencing many biochemical reactions, especially those involving synthesis of macromolecules, and therefore are absolutely required for normal and tumor cell growth. Considerable work has demonstrated the polyamine metabolic pathway to be a rational target for antineoplastic drug development. However, one cannot unambiguously assign specific regulatory roles to polyamines simply on the basis of a correlation between an increase in polyamine synthesis and other biochemical variations induced by the same signal. Therefore isolation and characterization of mutant somatic cells carrying specific defects in polyamine metabolism offers a new approach to this problem.

Folic acid is synthesised by plants and micro-organisms but not by animals, for which it is therefore essential in the diet. Major functions of the folates include participation in biosynthesis of purine and pyrimidine bases and therefore in nucleotide and nucleic acid metabolism. This function is especially critical at times of rapid cell growth and division, when demand for nucleic acid biosynthesis is highest. A range of anti-cancer drugs interfere with reactions which utilize H4-folate coenzymes and are effective because they interfere with nucleotide biosynthesis. In general, rapidly-dividing cells such as aggressive cancer cells are therefore targeted by the anti-folates.

POTENTIAL ADVANTAGES/USES: This group of cell lines offers a powerful tool to Cancer researchers and pharmaceutical companies in identifying and developing novel drug candidates to treat a variety of cancers. Compared to the existing cell lines with similar properties, both cell lines are totally deficient in transporting ability in their respective pathways and therefore provide cleaner and more definitive readouts without complications due to residual activity.

DEVELOPMENTAL STAGE: Fully developed 

Reference Numbers: UWO-AF-002; UWO-AF-003

Not patented. 

Available for out-licensing. A collaborative research approach involving the inventor would also be considered.