Dactinomycin resistance

Dactinomycin is useful against several tumors especially Wilms tumor of the kidney and rhabdomyosarcoma. Wilms tumor normally requires a combination of surgery, x-ray irradiation, and dactinomycin plus vincristine [57-22-7] or other antitumor agents. Resistance of the multidmg... 

Unfortunately, many human cancers have a large proportion of cells in the resting phase, and these cells are also resistant to the class 3 agents, which include cyclophosphamide, dactinomycin, and fluorouracil. 

Dactinomycin (actinomycin D, Cosmegen) is one of a family of chromopeptides produced by Streptomyces. It is known to bind noncovalently to double-strand DNA by partial intercalation, inhibiting DNA-directed RNA synthesis. The drug is most toxic to proliferating cells, but it is not specific for any one phase of the cell cycle. Resistance to dactinomycin is caused by decreased ability of tumor cells to take up and retain the drug, and it is associated with cross-resistance to vinca alkaloids, the anthracyclines, and certain other agents (multidrug resistance). 

Resistance to vinca alkaloids has been correlated with a decreased rate of drug uptake or an increased drug efflux from these tumor cells. Cross-resistance usually occurs with anthracycUnes, dactinomycin, and podophyllotoxins. 

Dactinomycin is used against ihabdomyasarcoma and Wilms tumor in children. It can be liicsaving for women with choriocarcinoma resistant to methotrexate. In combination with vincristine and cyclophosphamide, it has received some use in. solid tumors in children. Toxic reaction.s include anorexia, nausea, and vomiting. Bone marrow depression, resulting in pancytopenia, may occur within a week after therapy. Alopecia, erythema, and tissue injury may ixtcur at the injection site. 

---