Abstract 5409: Protection of chemotherapy-induced myelosuppresion by cytotech labs API 31543
Authors: Narain Niven R. , Mauro Lucia M. , Caperton Caroline V. , Yunis Adel A. , McCook John P. , Jimenez Joaquin J. 
Published: June 2012

High pulses of Calcitriol have been demonstrated to treat myelodysplastic syndrome without hypercalcemia. We have previously demonstrated that calcitriol protects chemotherapy-induced alopecia without calcemic effects. We thus hypothesized that a regimen of non-hypercalcemic high pulses of API 31543, a formulation containing calcitriol, may protect the bone marrow and circulating progenitors without protecting the cancer cells. 5-day old Long Evans rats were injected with MIAC51, a chloroleukemic cell line. On day 21, rats were randomized into 3 groups for each chemotherapy regimen. Group I received vehicle, group II received 10 µg API 31543. A pulse dose of vehicle or API 31543 was given 4 days prior to chemotherapy administration. Groups I and II were separated on day 21 into 2 groups and received the following chemotherapies: cyclophosphamide (CTX; 150mg/kg), cyclophosphamide and doxorubicin (CTX/DOXO; 100 mg/kg, 25 mg/kg, respectively) and cyclophosphamide, doxorubicin and paclitaxel, (CTX/DOXO/PAC 100 mg/kg, 25 mg/kg, 10 mg/kg, respectively). Starting on day 20 through day 32, complete granulocyte counts were then assessed. Baseline absolute neutrophil counts (ANC) prior to chemotherapy administration ranged from 3621 ±154 mm3 to 3000 ±254 mm3. Once chemotherapy was administered, ANC values dropped significantly between days 24 and 27. For CTX and vehicle the nadir ANC was 10% of the normal values. In contrast, the nadir of CTX and API 31543 was close to the normal count. In the group receiving CTX/DOXO, ANC was also reduced by 90%. For CTX/DOXO and vehicle nadir ANC was less than 10% of normal counts, while groups receiving CTX/DOXO and API 31543 were normal. Similarly, in groups receiving CTX/DOXO/PAC and vehicle, nadir ANC was less than 10%, while in groups receiving CTX/DOXO and API 31543 ANC values were normal. On day 32, a complete leukocyte count was performed in all animals and those positive for MIAC51 were sacrificed. Bone marrow cultures were performed on days 22, 25 and 32. Bone marrow cultures supported the ANC data. We therefore performed the same experiments on adult rats to mimic the multiple courses of chemotherapy. For the second cycle of chemotherapy, survivors were re-randomized and treated with the same chemotherapy regimens. Neutrophil counts were measured as previously described. The second pulse of API 31543 was administered on day 48, and chemotherapy was started. On day 52, rats were re-randomized for each chemotherapy regimen. Group I received vehicle only, group II received 20 µg API 31543. Results with the both regimens and all chemotherapies were similar. These results indicate that API 31543 significantly decreases the nadir ANC and confers bone marrow protection against chemotherapy, while not protecting the cancer cell. The data herein supports further development of this work and suggest that API 31543 may be a potential clinical agent for prevention of chemo-induced myelosuppression.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5409. doi:10.1158/1538-7445.AM2011-5409