Evaluation of topotecan and etoposide for non-Hodgkin lymphoma: correlation of topoisomerase-DNA complex formation with clinical response.
BACKGROUND
Topotecan, a topoisomerase I inhibitor, acts by stabilizing the topoisomerase DNA cleavage complex. Etoposide, a topoisomerase II inhibitor, mediates antitumor activity by stabilizing cleavage complex formed between topoisomerase II and DNA. These two agents have therapeutic activity in non-Hodgkin lymphoma. The authors report Phase I data of topotecan and etoposide combination for patients with recurrent or refractory non-Hodgkin lymphoma and correlation of topoisomerase-DNA complex formation to clinical response.


METHODS
Twenty-two patients with recurrent or refractory aggressive non-Hodgkin lymphoma were treated at four dose levels of topotecan (1 mg/m(2)/day to 2.5 mg/m(2)/day). Topotecan was given at a 30-minute infusion daily with etoposide 150 mg/m(2)/day, both for 5 days. Topoisomerase-DNA covalent complex formation was measured using in vivo link assay, whereas topoisomerase I, IIalpha, and IIbeta in RNA expression levels were determined by reverse transcription-polymerase chain reaction in blood samples. The relation of these levels to clinical response was studied.


RESULTS
The maximum tolerated dose of topotecan was 2.0 mg/m(2)/day for 5 days. Oropharyngeal mucositis was dose-limiting. Of 21 examinable patients, 3 patients achieved complete remission, and 5 patients achieved partial remission. Of six untreated patients who experienced a recurrence, three had complete remission, and the other three had partial remission. Drug-induced topoisomerase-DNA complex formation was observed throughout the treatment in blood samples of all the patients who responded. However, only 4 of 13 patients, who did not respond, formed covalent complex at all time points. This was statistically significant (P = 0.024). In all patients, expression levels of topoisomerase I and IIbeta mRNA remained similar to pretreatment levels, whereas topoisomerase IIalpha mRNA levels decreased dramatically by the third day.


CONCLUSIONS
The recommended Phase II dose of topotecan with etoposide of 150 mg/m(2)/day for 5 days was 2.0 mg/m(2)/day for 5 days. Topoisomerase-DNA complex formation correlated with response to treatment.
Kancherla
R R
RR
Zalmen A. Arlin Cancer Institute, Division of Oncology/Hematology, Department of Medicine, Rm 250 Munger Pavilion, New York Medical College, Valhalla, NY 10595, USA. ram_kancherla@nymc.edu
Nair
J S
JS
Ahmed
T
T
Durrani
H
H
Seiter
K
K
Mannancheril
A
A
Tse-Dinh
Y C
YC
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D004264:DNA Topoisomerases, Type I / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism*; D004268:DNA-Binding Proteins; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
D000951:Antigens, Neoplasm; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D012333:RNA, Messenger; D005047:Etoposide; D019772:Topotecan; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II