Theophylline, pentostatin (Nipent), and chlorambucil: a dose-escalation study targeting intrinsic biologic resistance mechanisms in patients with relapsed lymphoproliferative disorders.
In spite of the chemosensitivity seen with the initial treatment of malignant lymphoid disorders, relapse is common and death most often occurs as a result of disease progression. This is related to a multitude of resistance mechanisms associated with the various lymphoproliferative disorders. As a result, therapies targeting intrinsic drug-resistance mechanisms are evolving and have become an active area of research. In vitro studies of human chronic lymphocytic leukemia cells incubated with theophylline, a phosphodiesterase inhibitor, resulted in downregulation of bcl-2 concomitant with induction of apoptosis. We describe the preclinical basis for a novel combination therapy involving pentostatin (Nipent; SuperGen, San Ramon, CA), chlorambucil, and theophylline in the treatment of patients with relapsed chronic lymphoproliferative disorders. An ongoing study based on such justification, which is currently accruing patients, is also described. Results from this trial appear promising, and a phase II study is now being planned.
Byrd
J C
JC
Hematology/Oncology Department, Walter Reed Army Medical Center, Washington, DC 20307, USA.
Grever
M R
MR
Waselenko
J K
JK
Willis
C R
CR
Park
K
K
Goodrich
A
A
Lucas
M A
MA
Shinn
C
C
Flinn
I W
IW
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002423:Cause of Death; D002699:Chlorambucil / Q000008:administration & dosage*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D018450:Disease Progression; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019254:Genes, bcl-2 / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007938:Leukemia / Q000188:drug therapy*; D008223:Lymphoma / Q000188:drug therapy*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D015649:Pentostatin / Q000008:administration & dosage*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage*; D013806:Theophylline / Q000008:administration & dosage*
D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D007166:Immunosuppressive Agents; D010726:Phosphodiesterase Inhibitors; D002699:Chlorambucil; D015649:Pentostatin; D013806:Theophylline