The Clinical Development of 9‐Aminocamptothecin

Abstract

9-Aminocamptothecin (9-AC) is a topoisomerase I-targeting agent first synthesized by Wani and Wall in 1986. Because of its potent in vitro effects and promising preclinical activity in colorectal cancer animal models, it was designated a high-priority compound for further drug development by the NCI. In 1993, 9-AC first entered clinical trials as a 72-hour intravenous (i.v.) infusion. Predictable myelosuppression was the major dose-limiting toxicity, and pharmacokinetic studies showed a relatively short plasma half-life and unstable lactone ring. Unfortunately, phase II studies using this schedule showed minimal or no activity in tumors such as colorectal and lung cancer. Modest activity was observed in ovarian cancer and in refractory lymphomas. Efforts to improve systemic drug exposure by utilizing alternative schedules of administration of 9-AC such as prolonged, continuous intravenous infusions have also been tested. However, phase II studies of 120-hour weekly infusions of 9-AC have not shown improved activity against solid tumors such as colorectal cancer. More recently, a daily times 5 days i.v. administration schedule has been tested. Currently, further development of intravenously administered 9-AC for the treatment of colorectal cancer is not promising. Thus, topotecan and irinotecan remain the only two successfully developed topoisomerase I-targeting drugs in the United States. This experience with 9-AC raises important questions regarding how to best select new topoisomerase I-targeting drugs for future clinical development.

Natural Products as Cytotoxic Agents

“…After considerable effort it was discovered that placing substituents at the C9-and C11-positions considerably decreased serum protein binding, even with the lactone-ring opened analogs, and yet this did not interfere with antitumor activity. Among the analogs that have received clinical examination, but have not yet been marketed are lurtotecan (26), 9-nitro and 9-aminocamptothecin [258], and DX-8951f [259]. A number of other analogs stand out from the many that have been made.…”

A Predictive Model of Human Myelotoxicity Using Five Camptothecin Derivatives and the In vitro Colony-Forming Unit Granulocyte/Macrophage Assay

“…DX-8951f is being evaluated currently in Phase III clinical trials. Myelosuppression, especially neutropenia, is the principal dose-limiting toxicity of the camptothecin derivatives, such as DX-8951f, topotecan (3, 15, 16), 9-aminocamptothecin (4,17,18), and camptothecin (19,20). In clinical studies, camptothecin derivative-induced myelosuppression can be readily managed by administering granulocyte colony-stimulating factor.…”

Synthesis and cytotoxicity of phenyl-vinyl derivatives of 4,6,6-trimethyl-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile

“…It was interesting to find that a series of compounds having high (15,(3)(4)(5) or modest (2, 10, 23, 25) cytotoxicity towards tumor cells substantially induced the formation of nitric oxide in them (Table 4).…”

“…This compound showed a marked cytotoxic effect on the studied tumor cells (LC 50 10 µg/ml). With the aim of increasing the cytotoxicity and the selectivity of cytotoxic activity of styryl cyanolactams we have synthesized a series of mono- (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) and disubstituted (21)(22)(23)(24)(25)(26) phenyl derivatives (Tables 1 and 2) and studied their cytotoxicity on the two tumor cell lines HT-1080 and MG 22A as well as NIH 3T3 normal mouse fibroblasts which also served for evaluating the compound toxicity via the alternative method of determining LD 50 [33]. Condensation of lactam 1 with benzaldehydes was carried out in ethanol in the presence of a catalytic amount of NaOH (molar ratio of δ-lactam-aldehyde-NaOH 1:(1-2):(0.0625-0.25), respectively) at a temperature of 25-78ºC (Table 1).…”

“…A δ-lactam ring is included in camptothecin series antitumor preparations (inhibitors of topoisomerase I [10] -irinotecan [10,11], rubitecan [12], topotecan [10,13], exatecan [14], and its metabolite 9-aminocamptothecin [15], silatecan [16], and also inhibitors of dihydrofolate reductase (pemetrexed [17]), thymidyl synthetase (raltitrexed [18]), and farnesyl transferase (tipifarnib [19]). A δ-lactam ring occurs in the structure of an immunoregulator [20] and the antiangiogenic agent roquinimex [21].…”