Capizzi R L, Powell B L
Semin Oncol. 1987 Jun;14(2 Suppl 1):40-50.
In consideration of the full spectrum of hematologic and nonhematologic toxicity juxtaposed to the response rates (Tables 2-5), it appears that for relapsed patients with AML, six to eight consecutive doses of HDara-C or four doses started on days 1 and 8 have the optimal therapeutic index. These regimens are associated with a 25% CR rate and have comparable tolerable and reversible toxicity spectra. An increase in the total number of doses to 12 does not appear to increase the remission frequency in relapsed patients but does decidedly increase the spectrum, frequency, and severity of toxic manifestations. Studies of important pharmacologic determinants such as membrane transport and cellular accumulation of ara-CTP suggest that a lower unit dose may be just as effective, an approach that could potentially lower the frequency and severity of toxicity. However, these concepts must be tested in suitably designed clinical trials. In contrast to the response rate noted in patients with relapsed AML, patients with refractory AML have a substantially lower CR rate (approximately 10%) when treated with HDara-C alone. These lower CR rates are comparable to those reported for other recently introduced new drugs such as m-AMSA and mitoxantrone. In this setting of primary refractory leukemia, multi-institutional and cooperative group trials of HD-ara-C----ASNase show a consistently higher response rate in the range of 30% to 50%. Why ASNase should especially contribute to this particular group is unknown at present. Studies show that the gene for asparagine synthetase is repressed in AML cells. It is speculated that in the initial leukemia cell population (as encountered in refractory AML), the gene for asparagine synthetase is repressed and hence, the leukemia is sensitive to ASNase. In contrast, in the relapsed patient with recurrent leukemia, the gene for asparagine synthetase may be derepressed and the leukemia would be ASNase-insensitive. The therapeutic index of HDara-C----ASNase is schedule dependent. In leukemic mice, pretreatment or concurrent administration of ASNase and HDara-C leads to antagonism of both the therapeutic and toxic effects of HDara-C. These effects are consistent with similar effects of other protein synthesis inhibitors on ara-C toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)
考虑到与缓解率相关的血液学和非血液学毒性的全貌（表2 - 5），对于复发的急性髓系白血病（AML）患者，连续六至八剂大剂量阿糖胞苷（HDara - C）或在第1天和第8天开始的四剂似乎具有最佳治疗指数。这些方案的完全缓解（CR）率为25%，且具有相当的可耐受和可逆毒性谱。将总剂量增加到12剂似乎并不会增加复发患者的缓解频率，但确实会明显增加毒性表现的范围、频率和严重程度。对重要药理学决定因素的研究，如ara - CTP的膜转运和细胞蓄积，表明较低的单位剂量可能同样有效，这种方法有可能降低毒性的频率和严重程度。然而，这些概念必须在设计合理的临床试验中进行验证。与复发AML患者的缓解率不同，难治性AML患者单独使用HDara - C治疗时的CR率显著较低（约10%）。这些较低的CR率与其他近期引入的新药如m - AMSA和米托蒽醌所报道的相似。在原发性难治性白血病的情况下，HD - ara - C联合门冬酰胺酶（ASNase）的多机构和协作组试验显示缓解率持续较高，在30%至50%范围内。目前尚不清楚为什么ASNase对这一特定群体特别有效。研究表明，天冬酰胺合成酶基因在AML细胞中受到抑制。据推测，在初始白血病细胞群体中（如在难治性AML中所见），天冬酰胺合成酶基因受到抑制，因此白血病对ASNase敏感。相反，在复发的白血病患者中，天冬酰胺合成酶基因可能会去抑制，白血病对ASNase不敏感。HDara - C联合ASNase的治疗指数取决于给药方案。在白血病小鼠中，ASNase与HDara - C的预处理或同时给药会导致HDara - C的治疗和毒性作用均受到拮抗。这些作用与其他蛋白质合成抑制剂对阿糖胞苷毒性的类似作用一致。（摘要截选至400字）
