Initial experience with AMSA as single agent treatment against malignant lymphoproliferative disorders

Abstract

Thirty previously treated adults with lymphoma received AMSA as single agent therapy. All patients had previously received adriamycin- containing chemotherapy regimens and either failed to respond initially or responded but subsequently relapsed. The dose used was 40 mg/sq m.i.v. daily x3. For patients with compromised marrow reserve or elevated bilirubin, a 25% reduction was used. Ten of 30 patients achieved an objective response (3 CR, 3 PR, and 4 less than PR). Of the 3 patients achieving a complete remission, 2 with histiocytic lymphoma remain in remission and are currently off treatment at 14+ and 18+ mo. The response rate to AMSA was found to correlate with the type of response to frontline therapy and also with the number of previous relapses. Complete remissions on AMSA were only seen in patients who had achieved a CR on frontline treatment and who were treated on their first relapse. AMSA is an active drug against malignant lymphoma and deserves further investigation.

Synthesis and Structure−Activity Relationships of Potential Anticancer Agents: Alkylcarbamates of 3-(9-Acridinylamino)-5-hydroxymethylaniline

“…Since AHMA-ethylcarbamate was shown to be the most potent among AHMA-alkylcarbamate derivatives, AHMA derivatives with substituent(s) at acridine ring were converted into their ethylcarbamate derivatives for SAR studies (Table 1). It is also important to note that all AHMA-ethylcarbamates (18 and 23-34) were more potent than their corresponding AHMA derivatives (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16); among these compounds, derivative 34 was the most potent with an IC 50 value of 0.0023 µM (10 times more potent than AHMA). Our present results suggest that introduction of an alkylformate function to the NH 2 group of AHMA forming AHMA-alkylcarbamates may alter the lipophilicityhydrophilicity balance as well as the interaction of the compound with the active site of Topo II enzyme, thereby possibly affecting the antitumor activity of 9-anilinoacridine derivatives.…”

“…To find AHMA derivatives with superior antitumor activity as compared to the parent compound, we synthesized a series of AHMA derivatives with monoand disubstituents on the acridine ring and carried out SAR studies. Table 1 shows the in vitro cytotoxicity of the parent compound AHMA (3) and its derivatives with mono-or disubstituent(s) on the acridine ring (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) against the growth of human leukemic HL-60 cell line in culture. In the series of AHMA derivatives with a monosubstituent at C4′ of the acridine ring, AHMA with a C4′-OMe or C4′-Me substituent (5 and 6) or with a chargeable side chain C4′-CONH(CH 2 ) 2 NMe 2 (8) were more cytotoxic than AHMA by 2-4 times, while AHMA with C4′-CONHMe, C4′-NO 2 , or C4′-halogen substituents (compounds 7, 9, and 10-12, respectively) were less potent than the parent compound AHMA.…”

“…Table 1 shows the in vitro cytotoxicity of the parent compound AHMA (3) and its derivatives with mono-or disubstituent(s) on the acridine ring (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) against the growth of human leukemic HL-60 cell line in culture. In the series of AHMA derivatives with a monosubstituent at C4′ of the acridine ring, AHMA with a C4′-OMe or C4′-Me substituent (5 and 6) or with a chargeable side chain C4′-CONH(CH 2 ) 2 NMe 2 (8) were more cytotoxic than AHMA by 2-4 times, while AHMA with C4′-CONHMe, C4′-NO 2 , or C4′-halogen substituents (compounds 7, 9, and 10-12, respectively) were less potent than the parent compound AHMA. Compound 9 bearing a strong electron-withdrawing nitro function decreased the cytotoxicity of AHMA dramatically.…”

“…In contrast to m-AMSA derivatives, 6 introduction of the monosubstituent OMe or Me to the C4′-position enhanced the in vitro antitumor activity of AHMA, while introduction of disubstituents OMe or Me and CONHMe to C4′-and C5′-positions, respectively, decreased the activity. Unlike N-[2-(N,N-dimethylamino)ethyl]-9-aminoacridine-4-carboxamide, 4 the in vitro antitumor activity of N-[2-(N,N-dimethylamino)ethyl]-AHMA-4-carboxamide (8) was not parallelyl increased by adding OMe or Me to the C5′-position, since compound 14 was about 3 times less cytotoxic than 5, while compound 16 was 2 times more potent than the parent compound.…”

“…Members of the class of 9-anilinoacridine derivatives have been synthesized as potential topoisomerase II (Topo II)-mediated anticancer agents. − Structure−activity relationships (SAR) including the position of substituent(s), chemical and physical properties, lipophilicity−hydrophilicity balance, etc., have also been investigated by Atwell and Baguley et al − The first 9-anilinoacridine derivative to achieve clinical use as an anticancer agent was amsacrine ( m -AMSA, 1 ; Chart ) to treat leukemia and lymphoma. − However, m -AMSA lacks broad-spectrum clinical activity and has a low therapeutic index. In addition, this agent has been difficult to formulate because of its low aqueous solubility.…”