Mechanism of resistance of cyclophosphamide

Cyclophosphamide is one of the most active chemotherapeutic drug used in the treatment of many cancerous conditions. Sometimes it may resistant and cannot act properly. As a result, treatment failure developed. Resistance to cyclophosphamide is multifactorial with a diverse spectrum of mechanisms observed in cancer treatment which includes;

► Cell may uptake reduced amount of drug and this small amount of drug fails to stop the growth of cancer cells.

► Cyclophosphamide is activated by liver cytochrome P-450 oxidase system. Sometimes, the activity of these enzymes may be reduced. Therefore, the inactive cyclophosphamide cannot convert into appropriate amount of active cytotoxic metabolites which ultimately fails to stop the growth of cancer cells.

► Within the cells, the level of sulfhydryl proteins including glutathione and glutathione associated enzymes may be increased. The high level of sulfhydryl proteins may interact with the active metabolites of cyclophosphamide and prevent its binding to target DNA. As a result, cyclophosphamide-induced DNA lesions is hampered and ultimately cancer cells damage is prevented.

► The activity of aldehyde dehydrogenase enzyme in the body may be increased. The overactive aldehyde dehydrogenase appears to be involved directly in the detoxification of cyclophosphamide and its active metabolites. As a result, detoxified cyclophosphamide cannot stop the growth of cancer cells.

► Sometimes the activity of DNA repairing enzymes increased. When cyclophosphamide produces DNA lesions, the overactive DNA repairing enzymes repair the lesions DNA, possibly through the nucleotide excision repairing process and prevent the cancer cells from dying.