Teniposide in the treatment of leukemia: a case study of conflicting priorities in the development of drugs for fatal diseases.
Teniposide, a semisynthetic epipodophyllotoxin, was found to be highly active against murine leukemias, and the combination of teniposide with cytosine arabinoside (ara-C) was curative in murine leukemia models. The antitumor activity in preclinical models prompted introduction of teniposide into the clinic in 1971. Although teniposide as a single agent rarely produced a complete remission in heavily pretreated leukemia patients, teniposide plus ara-C produced complete remissions in some patients with refractory and relapsed acute lymphoblastic leukemia (ALL). Innovative front-line and salvage regimens using teniposide have been developed that incorporate a multi-drug strategy with early intensification, rotation of drug combinations in maintenance, and regional therapy in an effort to improve the cure rate in leukemia. However, as the complexity of these regimens increases, the contribution of an individual component such as teniposide becomes less clear. Although some of these regimens for newly diagnosed and relapsed ALL are now thought to represent the best available therapy, teniposide remains an investigational agent. In this review, we outline and discuss the conflicts arising from the need to answer drug-specific issues, and, at the same time, facilitate the implementation of innovative, curative regimens.
Grem
J L
JL
Investigational Drug Branch, National Cancer Institute, Bethesda, MD 20892.
Hoth
D F
DF
Leyland-Jones
B
B
King
S A
SA
Ungerleider
R S
RS
Wittes
R E
RE
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003561:Cytarabine / Q000008:administration & dosage; D004334:Drug Administration Schedule; D006801:Humans; D007945:Leukemia, Lymphoid / Q000188:drug therapy* / Q000401:mortality; D011034:Podophyllotoxin / Q000031:analogs & derivatives*; D013713:Teniposide / Q000008:administration & dosage / Q000627:therapeutic use*
D003561:Cytarabine; D013713:Teniposide; D011034:Podophyllotoxin