C Segura1, E Bandrés2, I F Trocóniz1, J GarcÃa-Foncillas2,O Sayar1, C Dios-Vieitez1, M J Renedo1, M J Garrido1
1Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Pamplona.
Propose: To increase the understanding of the dynamic regulation involved in the hematopoietic alterations observed after the administration of topotecan (TPT) by fitting simultaneously im- and mature B cells.
Methods: Two groups of BDIX rats bearing tumor were used. Group I and II received saline or 6mg/kg of TPT. 30 days later, group II was divided in other two groups receiving TPT as a single 6mg/kg dose or as two consecutive administrations of 3mg/kg dose. Blood samples were withdrawn from each animal every 48h for five weeks. In each sample, the absolute number of leukocytes measured by Coulter counter and different lymphocyte subsets measured by flow-cytometric analysis were quantified. Absolute B lymphocyte counts were calculated on the basis of total leukocyte number. The pk of TPT was previously evaluated in a separate group of rats.
Results: It was expected that temporal alterations in the mature circulating cells are preceded by similar changes in immature cells. However, the results showed that after TPT treatment both type of cells decreased in parallel reaching the nadir at day 3-4, but while mature B-cells returned to baseline at day 8, immature B-cells were maintained at very low levels until approximately day 9 increasing slowly to reach baseline 21 days after TPT administration. The time course of the immature cells was described with a model incorporating a self-renewal of the stem cells, a maturation chain, a feedback mechanism, and a drug effect over the proliferation of the stem cells. [1] To fit the mature cell data an extra compartment (located outside the maturation chain) was incorporated into the model. Such compartment would resemble the spleen, where mature B-cells with a relative long life span, are stored in a number higher than in blood or bone marrow. [2] A decrease in the number of circulation mature B cells triggers the release from the spleen to the blood stream, allowing therefore a faster recovery of the mature B cells.
Conclusion: The proposed model could describe simultaneously two different stages of B cell providing new aspects about the dynamics of the hematopoietic system.
References:
[1] Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO (2002) J Clin Oncol 20: 4713-21.
[2] Zandvoort A, Lodewijk ME, Klok PA, Dammers PM, Kroese FGM, Timens W (2001) Clin Exp Immunol; 124: 172-9.
Reference: PAGE 13 () Abstr 536 [www.page-meeting.org/?abstract=536]
Poster: poster