L1210 leukemia i. v. implanted as a model for testing short-chain nitrosourea analogs

Abstract

A total of 11 newly synthesized 2-chloroethyl-nitrosoureas and 1 2-fluoroethyl-nitrosourea with short-chain substituents were tested for their cytostatic activity on the L1210 mouse leukemia in comparison to clinically used nitrosoureas. Initial experiments showed advantages of the i.v. route for tumor inoculation. Therefore, the anatomical generalisation of tumor cells after i.v. injection was studied by bio-assay. Tumor cell determinations in different organs were 10 to 100 times higher compared with i.p. implantation. Of the new compounds 10 showed marked cytostatic activity in this tumor model by producing cures, and 5 of them must be considered as superior to BCNU, the most commonly used nitrosourea.

A Critical Appraisal of the Evolution ofN-Nitrosoureas as Anticancer Drugs

“…By contrast, the glutarimide analog 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1nitrosourea (PCNU, 257) had a high activity against both the ip-and ic-inoculated L1210 in mice (Table 17). 96,113 This lipophilic drug had lower carbamoylating and higher alkylating activities 96 than other nitrosoureas but similar cytotoxic and DNA repairinhibiting capabilities. 229 A review 230 was published on the anticancer activity, toxicology, pharmacokinetics, and phase I clinical studies of PCNU (257).…”

“…This result supported the contention 6 that either a five- or six-membered ring or a 2-haloethyl moiety attached to the unnitrosated nitrogen is essential for high anticancer activity. The introduction at the N3-position of ester ( 44 ), nitrile ( 45 , 46 ), ketone ( 47 ), amine ( 48 ), and substituted amines ( 49 − 51 ) moieties have been reported (Table ). ,,, Some of these compounds e.g. 48 − 51 , are actually semicarbazide and carbazide derivatives.…”

“…The compound was found to have a moderate activity against the CNS cancer ependymoblastoma with a 140% ILS, but the clinical drugs BCNU ( 33 ) and MeCCNU ( 138b ) were much more effective against both cancer lines. By contrast, the glutarimide analog 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea (PCNU, 257 ) had a high activity against both the ip- and ic-inoculated L1210 in mice (Table ). , This lipophilic drug had lower carbamoylating and higher alkylating activities 96 than other nitrosoureas but similar cytotoxic and DNA repair-inhibiting capabilities . A review was published on the anticancer activity, toxicology, pharmacokinetics, and phase I clinical studies of PCNU ( 257 ).…”

“…In comparison, the carbohydrate CZT ( 368 ) was only marginally active in this iv system. This result is also reflected in the disappointing clinical trials of CZT ( 368 ) using the iv regimen ) and a variety of solid tumors.…”

“…The introduction at the N3-position of ester (44), nitrile (45,46), ketone (47), amine (48), and substituted amines (49)(50)(51) moieties have been reported (Table 2). 43,44,112,113 Some of these compounds e.g. 48-51, are actually semicarbazide and carbazide derivatives.…”