Low-dose chemotherapy delays relapse of a dominated and resistant sub-population in a heterogeneous human SCLC xenograft in nude mice.
We investigated the influence of cellular heterogeneity on the response to low-dose BCNU chemotherapy of an artificially mixed human small-cell lung cancer (SCLC) xenograft in nude mice containing a BCNU-sensitive and dominating sub-population and a BCNU-resistant and undetectable (dominated) sub-population. The cell lines differed in DNA content, making them distinguishable by DNA flow cytometry (FCM). After 3 weeks of tumor growth, the mice were stratified according to tumor size and randomized to 2 different low-dose treatments with BCNU or no treatment. After a further 3 to 4 weeks, a high-dose treatment (LD10) was given to both groups of treated tumors. Changes in the relative proportions of and cell lines in the tumors were measured by FCM on fine-needle tumor aspirates. At the time of low-dose treatment, all the tumors were totally dominated by the sensitive cells. A temporary response was seen after low-dose treatment. After the high-dose treatment, a similar short response was seen. In the non-treated group, the sensitive cells continued to dominate. At the time of tumor regrowth after the low-dose treatment, most of the tumors continued to be dominated by the sensitive population. At the time of progression after the response to the high-dose treatment, the resistant cell line was the predominant population. If compared with a single high-dose BCNU treatment, the response of tumors treated with a low dose was superior, indicating that the presence of a dominating and slower growing sub-population influenced the outcome of the treatment.
Aabo
K
K
University Institute of Pathological Anatomy, University of Copenhagen, Denmark.
Vindeløv
L L
LL
Christensen
I J
IJ
Spang-Thomsen
M
M
D000818:Animals; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000473:pathology; D002330:Carmustine / Q000008:administration & dosage / Q000627:therapeutic use*; D004273:DNA, Neoplasm / Q000032:analysis; D004351:Drug Resistance; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D002330:Carmustine