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Mechanism of Action
The mechanism of action of Elspar (asparaginase) is thought to be based on selective killing of leukemic cells due to depletion of plasma asparagine. Some leukemic cells are unable to synthesize asparagine due to a lack of asparagine synthetase and are dependent on an exogenous source of asparagine for survival. Depletion of asparagine, which results from treatment with the enzyme L-asparaginase, kills the leukemic cells. Normal cells, however, are less affected by the depletion due to their ability to synthesize asparagine.
The relationship between asparaginase activity and asparagine levels has been studied in clinical trials. In previously untreated, standard-risk ALL patients treated with native asparaginase in whom plasma enzyme activity was greater than 0.1 International Units/ml, plasma asparagine levels decreased from a pretreatment average level of 41 μM to less than 3 μM. In this study, cerebrospinal fluid asparagine levels in patients treated with asparaginase decreased from 2.8 μM (pretreatment) to 1.0 μM and 0.3 μM at day 7 and day 28 of induction, respectively.2
In a study 5 in patients with metastatic cancer and leukemia, daily intravenous administration of L-asparaginase resulted in a cumulative increase in plasma levels. Plasma half-life varied from 8 to 30 hours. Apparent volume of distribution was slightly greater than the plasma volume. Asparaginase levels in cerebrospinal fluid were less than 1% of concurrent plasma levels.
In a study 6 in which patients with leukemia and metastatic cancer received intramuscular L-asparaginase, peak plasma levels of asparaginase were reached 14 to 24 hours after dosing. Plasma half-life was 34 to 49 hours.
Edema and necrosis of pancreatic islets were observed in rabbits following a single, intravenous injection of 12, 500 to 50, 000 International Units Elspar (asparaginase) /kg (approximately equivalent to 25 to 100-fold the recommended human dose, when adjusted for total body surface area). These changes were not reflective of pancreatitis, and were not observed in rabbits following a single intravenous injection of 1000 International Units/kg (approximately equivalent to two times the recommended human dose, when adjusted for total body surface area).
Elspar (asparaginase) was evaluated in an open-label, multi-center, single-arm study in which 823 patients less than 16 years of age with previously untreated acute lymphoblastic or acute undifferentiated leukemia received Elspar (asparaginase) as a component of multi-agent chemotherapy for induction of first remission. Elspar (asparaginase) was administered at a dose of 6, 000 International Units/m²intramuscularly 3 times a week for a total of 9 doses.7 Of 815 evaluable patients, 758 (93%) achieved a complete remission. In a previous study, in a similar patient popula-tion, which utilized an initial induction chemotherapy regimen containing the same agents without Elspar (asparaginase) , 429 of 499 (86%) patients achieved a complete remission.
2. Avramis, VI; Sencer, S.; Periclou, AP; Sather, H.; Bostrom, BC; Cohen, L.J.; Ettinger, A.G.; Ettinger, L.J.; Franklin, J.; Gaynon, PS; Hilden, J.M.; Lange, B.; Majlessipour, F.; Mathew, P.; Needle, M.; Neglia, J.; Reaman, G.; Holcenberg, J.S.: A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study, Blood 99:1986-1994, 2002.
5. Ho, D.H.W.; Thetford, B.S.; Carter, C.J.K.; Frei, E., III:Clinical pharmacologic studies of L-asparaginase, Clin.Pharmacol. Ther. 11:408-417, May-June 1970.
6. Ho, D.H.W.; Yap, H.Y.; Brown, N.; Benjamin, R.S.; Friereich, E.J.; Blumenschein, G.R.; Bodey, G.P.:Clinical pharmacology of intramuscularly administered L-asparaginase, J.Clin.Pharmacol. 21: 72-78, Feb.-Mar. 1981.
7. Ortega, J.A.; Nesbit, M.E.; Donaldson, M.H.; Hittle, R.E.; Weiner, J.; Karon, M.; Hammond, D.: L-asparaginase, vincristine and prednisone for induction of first remission in acute lymphocytic leukemia, Cancer Research 37: 535-540, Feb. 1977.
Last reviewed on RxList: 10/10/2008
This monograph has been modified to include the generic and brand name in many instances.
Additional Elspar Information
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