2'-Deoxycoformycin (pentostatin) for lymphoid malignancies. Rational development of an active new drug.
A new antimetabolite, 2'-deoxycoformycin (pentostatin), has striking antitumor activity in several lymphoid neoplasms. Isolated from cultured soil organisms, this purine analogue is a potent inhibitor of adenosine deaminase (ADA), and is thus selectively toxic to lymphocytes. Early clinical trials showed that high doses of pentostatin caused severe and unpredictable toxicity, but responses in refractory lymphoid malignancies were encouraging. Careful pharmacologic studies led to the definition of a safe and effective low weekly dose, at which protracted ADA inhibition occurs in neoplastic cells. The most sensitive tumor identified is hairy cell leukemia, in which durable remissions are achieved in more than 90% of patients with a relatively brief course of treatment. Other responsive diseases include chronic lymphocytic leukemia, prolymphocytic leukemia, mycosis fungoides, and acute T-cell lymphoma or leukemia. Response has been seen in acute lymphocytic leukemia, but the higher doses required are substantially more toxic. Pentostatin is valuable for treatment of indolent lymphoid malignancies and may be useful in non-cancer-related lymphocyte research.
O'Dwyer
P J
PJ
Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Wagner
B
B
Leyland-Jones
B
B
Wittes
R E
RE
Cheson
B D
BD
Hoth
D F
DF
D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D002986:Clinical Trials as Topic; D003070:Coformycin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004341:Drug Evaluation; D006801:Humans; D007166:Immunosuppressive Agents; D007938:Leukemia / Q000188:drug therapy*; D008223:Lymphoma / Q000188:drug therapy*; D015649:Pentostatin; D012263:Ribonucleosides / Q000627:therapeutic use*
D058892:Adenosine Deaminase Inhibitors; D000964:Antimetabolites, Antineoplastic; D007166:Immunosuppressive Agents; D012263:Ribonucleosides; D003070:Coformycin; D015649:Pentostatin