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Pharmacologic marrow purging in murine T cell leukemia
E A Copelan1, S C Johnson, M R Grever
1Ohio State University, Bone Marrow Transplantation Program, Columbus 43210.
Abstract:
Deoxycoformycin in combination with deoxyadenosine was used to purge 6C3HED malignant T cells from murine marrow in vitro. Adenosine deaminase activity of 6C3HED cells was ablated by incubation with 10(-6) mol/L deoxycoformycin (dCF). During a 12-hour incubation with 10(-6) mol/L dCF and 10(-4) mol/L deoxyadenosine, tumor cells sequentially accumulated dATP, became depleted of NAD followed by ATP, then died. More than 5 logs of 6C3HED cells were killed as measured by survival of mice injected with treated tumor cells. Identical incubation of 5 x 10(6) marrow cells did not interfere with rescue of syngeneic lethally irradiated mice. Long-term survival was demonstrated in 12 of 14 mice that received marrow that had been contaminated with 5% 6C3HED cells, incubated with deoxycoformycin and deoxyadenosine, then used to rescue lethally irradiated mice. This murine model provides information not available from in vitro assays and may be useful in the development of strategies to purge malignant T cells from marrow.
Insights
Deoxycoformycin and deoxyadenosine effectively purged malignant T cells from murine marrow. This combination therapy offers a promising strategy for purging cancer cells from bone marrow for transplantation.
Area of Science:
- Biochemistry
- Immunology
- Cell Biology
Background:
- Malignant T cells pose a significant challenge in bone marrow transplantation.
- Effective purging of contaminating tumor cells is crucial for successful engraftment and patient survival.
Purpose of the Study:
- To investigate the efficacy of deoxycoformycin (dCF) in combination with deoxyadenosine for purging 6C3HED malignant T cells from murine marrow.
- To evaluate the safety and efficacy of this purging strategy in a murine bone marrow rescue model.
Main Methods:
- Murine 6C3HED malignant T cells were incubated with deoxycoformycin (10(-6) mol/L) and deoxyadenosine (10(-4) mol/L) for 12 hours.
- Cellular adenosine deaminase activity, nucleotide levels (ATP, dATP), and NAD levels were assessed.
- The purged marrow was used to rescue lethally irradiated syngeneic mice, with tumor cell contamination and long-term survival monitored.
Main Results:
- Incubation with dCF ablated adenosine deaminase activity in 6C3HED cells.
- Tumor cells accumulated dATP, depleted NAD and ATP, leading to cell death.
- Over 5 logs of 6C3HED cells were killed, with no interference to normal marrow cell rescue.
- 12 out of 14 mice receiving contaminated marrow treated with dCF and deoxyadenosine survived long-term.
Conclusions:
- Deoxycoformycin and deoxyadenosine combination is a potent method for purging malignant T cells from murine marrow.
- This purging strategy is compatible with bone marrow rescue and offers potential for clinical application in T-cell malignancies.
- The developed murine model is valuable for assessing strategies to purge malignant T cells from bone marrow for transplantation.