Circulating progenitor cell release and functional characterization after topotecan plus G-CSF and erythropoietin in small cell lung cancer patients.
Topotecan is a new antineoplastic agent active in ovarian cancer, with promising activity in small cell lung cancer and predictable toxicity. As a part of our ongoing attempt to optimize the use of disease-specific drugs as circulating progenitor cell (CPC) priming in solid tumors, we have evaluated the effects on CPC release of single-agent Topotecan followed by granulocyte colony-stimulating factor (G-CSF) + human recombinant erythropoietin (rhEPO), together with the cell cycle status of the collected CD34+ cells. Ten pretreated patients with small cell lung cancer received Topotecan (1 mg/m2, i.v. for 5 consecutive days) followed by G-CSF (5 microg/kg/day, s.c.) + rhEPO (10,000 I.U. daily, s.c.), starting 24 h after Topotecan. The combination was well tolerated and no relevant side-effects were recorded. On day +10 (range +9 to +11) after the last dose of Topotecan, the median WBC count and the CD34+ cell peak were 8.2 x 10(3) microl (range 4.9-13.9) and 55 microl (range 28-75), respectively. Using flow cytometry, a detailed cell cycle analysis was performed on these CD34+ cells. The cell cycle distribution was determined by DNA content coupled with bromodeoxyuridine incorporation analysis. Apoptosis was evaluated by quantitating DNA strand breaks. The percentage of CD34+ cells in active S-phase was 10.2+/-5%, while early apoptotic CD34+ cells were detected in a low percentage (5.5+/-3%). Topotecan followed by G-CSF + rhEPO mobilizes CPCs effectively. This sequence exerts a stimulation on CD34+ cell cycle with a protective effect from chemotherapy-induced apoptosis. Taken together, these data could be of value for the incorporation of Topotecan, as well as of the combination of G-CSF and rhEPO, into high-dose chemotherapy programs with CPC support.
Ferrari
S
S
A. Ferrata Institute of Internal Medicine and Medical Oncology, I. R.C.C.S. San Matteo University Hospital, I-27100 Pavia, Italy.
Danova
M
M
Porta
C
C
Comolli
G
G
Brugnatelli
S
S
Pugliese
P
P
Riccardi
A
A
Ascari
E
E
D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis; D001973:Bromodeoxyuridine; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D004359:Drug Therapy, Combination; D004921:Erythropoietin / Q000627:therapeutic use*; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007958:Leukocyte Count / Q000187:drug effects; D008175:Lung Neoplasms / Q000188:drug therapy*; D008875:Middle Aged; D010976:Platelet Count / Q000187:drug effects; D011994:Recombinant Proteins; D013997:Time Factors; D019772:Topotecan / Q000009:adverse effects / Q000627:therapeutic use*
D018952:Antigens, CD34; D011994:Recombinant Proteins; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D019772:Topotecan; D001973:Bromodeoxyuridine