Lethality to leukemia cell lines of DNA interstrand cross-links generated by Cloretazine derived alkylating species

Abstract

Cloretazine [1, 2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]-hydrazine; VNP40101M; 101M] is a relatively new prodrug with activity in elderly acute myelogenous leukemia patients. Its therapeutic action is due largely to the production of 1-(3-cytosinyl),2-(1-guanyl)ethane cross-links (G-C ethane cross-links) in DNA. The number of cross-links produced in three experimental leukemia lines (L1210, U937 and HL-60) were fewer than 10 per genome at their respective LC 50 concentrations. Only 1 in approximately 20,000 90CE molecules produce a crosslink in the AGT (O 6 -alkylguanine-DNA alkyltransferase) negative L1210 and U937 cell lines and 1 in 400,000 in the AGT positive HL-60 cell line.

Phase 3 randomized, placebo-controlled, double-blind study of high-dose continuous infusion cytarabine alone or with laromustine (VNP40101M) in patients with acute myeloid leukemia in first relapse

“…18,20,21 The preclinical development of laromustine was focused on the synthesis of an agent that generated an alkylating species that demonstrated antitumor activity with relatively less toxicity to normal tissues. 5,[7][8][9][10]27,28 The clinical development of laromustine in AML has evolved from a consistent demonstration, in both adult and pediatric patients with a variety of refractory solid tumors or hematologic malignancies, that myelosuppression is the dose-limiting toxicity, occurring at doses that incur relatively low extramedullary toxicity. [16][17][18][19][20][21] In 2002, after analysis of 31 trials of at least 20 patients each, Leopold and Willemze concluded that no chemotherapy regimen had been shown to be more effective than another for patients with relapsed AML.…”

“…[1][2][3] Laromustine (Onrigin, VNP40101M; Vion Pharmaceuticals Inc) is a sulfonylhdrazine alkylating agent selected for clinical development based on its broad antitumor activity in preclinical models. [4][5][6] Activated, it forms a chloroethylating group that preferentially targets the O 6 over the N 7 position of guanine, resulting in interstrand DNA cross-links. 7 In vitro, it produces more cross-links and fewer DNA single-strand nicks compared with carmustine and lomustine.…”

“…90CE rapidly produces an alkylating, chloroethylating species, similar to the species generated by carmustine. 4,5 Carmustine and laromustine produce different decomposition products as laromustine does not yield hydroxyethylating, vinylating, or aminoethylating species. Laromustine yields more than twice the molar yield of DNA cross-links than do the nitrosoureas.…”

“…The chlorethylating species responsible for laromustine's alkylation is relatively specific to the O 6 position of guanine, whereas carmustine (BCNU) and other alkylating agents, unlike laromustine, also alkylate the N 7 position of guanine. 4,5 Drugs that cause primarily N 7 alkylations exhibit one-thirtieth of the anticancer activity and the same mutagenic potential as their counterparts that form both N 7 alkylations and cross-links. [8][9][10][11] Laromustine does not generate hydroxyethyl alkylations of the O 6 position of guanine-these lesions are considered to be carcinogenic but therapeutically unimportant.…”

“…[8][9][10][11] Laromustine does not generate hydroxyethyl alkylations of the O 6 position of guanine-these lesions are considered to be carcinogenic but therapeutically unimportant. 5,11 Laromustine also inhibits the nucleotidyltransferase activity of purified human DNA polymerase beta, a principal enzyme of DNA base excision repair. 12 Alkylated DNA is often repaired via base excision repair in vivo.…”