To study the effect of isoprenoid and aliphatic saturated alcohols as modificator on benzoic nitrogen mustard, the intermediate 4-[N,N-bis(2-chloroethyl) amino] benzoic acid 4 was prepared in four steps utilizing p-amino benzoic acid as the starting material. Target compounds were synthesized by the catalytic esterification of DCC/DMAP and the structures of the six new esters were characterized by elemental analysis, 1H NMR, 13C NMR and MS. Antitumor activities were evaluated in vitro using MTT assay. The result showed that some derivatives were more potent than the intermediate 4, and compound 5c modified with dodecanol exhibited similar activity to the commercial drug melphalan.
Aminobenzoates ; chemical synthesis ; pharmacology ; Animals ; Antineoplastic Agents, Alkylating ; chemical synthesis ; pharmacology ; CHO Cells ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cricetinae ; Cricetulus ; Humans ; Inhibitory Concentration 50 ; K562 Cells ; Melanoma, Experimental ; pathology ; Melphalan ; pharmacology ; Nitrogen Mustard Compounds ; chemical synthesis ; pharmacology

OBJECTIVETo confirm the enhancing effect of excision repair cross complementing rodent repair deficiency gene 2 (ERCC2) on alkylating agents resistance.

METHODSThe authors constructed a pcDNA3-ERCC2 plasmid. The pcDNA3-ERCC2 was transfected into a selected ERCC2 negative human glioma cell line, SKMG-4, using liposome-mediated transfection. After G418 selection, a stable transfected cell line was obtained and tested for cytotoxicity of several alkylating agents.

RESULTSThe stable transfectant was obtained and confirmed by RT-PCR as well as Western blot analysis to be strongly expressing ERCC2 at both mRNA and protein levels. The IC(90) ( micro mol/L) of two alkylating agents, cisplatin and melphalan, increased from 1.0 to 1.75 (75%) and 5.6 to 9.0 (61%), respectively, compared with control cell line.

CONCLUSIONThe present data provided evidences and confirmed the authors' previous results that ERCC2 contributes, at least partially, to alkylating agent resistance in human glioma cell line.

Antineoplastic Agents, Alkylating ; pharmacology ; Cisplatin ; pharmacology ; DNA Helicases ; DNA-Binding Proteins ; Drug Resistance, Neoplasm ; genetics ; Glioma ; Humans ; Melphalan ; pharmacology ; Proteins ; genetics ; Transcription Factors ; Transfection ; Tumor Cells, Cultured ; Xeroderma Pigmentosum Group D Protein

Immunoglobulin (Ig) D multiple myeloma (MM) accounts for 2% of all MM cases and has been reported to be associated with poor prognosis compared with other MM subtypes. The aim of the present study was to compare the effects of high-dose melphalan treatment and autologous stem cell transplantation (ASCT) on the survival of patients with IgD MM and patients with other MM subtypes. Between November 1998 and January 2005, a total of 77 patients with MM who underwent ASCT at the Asan Medical Center were enrolled in this study. High-dose melphalan (total 200 mg/m2) was used as high-dose chemotherapy. The study population was divided into two groups based on MM subtype: those with IgD MM; and those with other MM subtypes. A total of 8 patients with IgD MM were identified, accounting for about 10% of the study population. Thirty-six patients (47%) had IgG MM, 17 patients (22%) had IgA MM, and 16 patients (20%) had free light-chain MM. The two groups were similar in baseline characteristics. The median follow-up was 17 months and the median overall survival (OS) was 39 months. In the IgD MM group, median eventfree survival (EFS) and OS were 6.9 and 12 months, respectively. In the patients with other MM subtypes, median EFS and OS were 11.5 and 55.5 months (p=0.01, p<0.01), respectively. Multivariate analysis of all patients identified IgD subtype (p=0.002) and Southwest Oncology Group (SWOG) stage 2 or greater at the time of ASCT (p=0.01) as adverse prognostic factors for survival. In this small study at a single center in Korea, patients with IgD MM had poorer outcomes after ASCT than did patients with other MM subtypes.
Adult ; Aged ; Female ; Humans ; Immunoglobulin D/*chemistry ; Male ; Melphalan/*pharmacology ; Middle Aged ; Multiple Myeloma/*drug therapy/genetics/*immunology ; Myeloablative Agonists/*pharmacology ; Prognosis ; Retrospective Studies ; Stem Cell Transplantation/*methods ; Transplantation, Autologous ; Treatment Outcome