ABSTRACT
Four second-generation Illudin analogues were synthesized and tested for antitumor activity using a metastatic lung carcinoma xenograft model resistant to conventional antitumor agents. One analogue, the parent illudofulvene-derivative called Acylfulvene, inhibited xenograft primary tumor growth and prolonged life span of tumor-bearing animals when administered i.p. or i.v. The efficacy of Acylfulvene exceeded that of mitomycin C, cisplatin, paclitaxol, the parent compound Illudin S, and an earlier analogue, dehydroilludin M. Promising features of this new analogue are: (a) the retention of in vitro activity against a variety of mdr tumor phenotypes including gp170+, gp150+, GSHTR-Pi, topoisomerase I, and topoisomerase II mutants; and (b) an apparent selective cytotoxicity toward cells deficient in either ERCC2 or ERCC3 DNA helicase activity.
Subject(s)
Adenocarcinoma/drug therapy , Antibiotics, Antineoplastic/pharmacology , DNA Helicases/deficiency , DNA-Binding Proteins/metabolism , Drosophila Proteins , Lung Neoplasms/drug therapy , Proteins/metabolism , Sesquiterpenes/pharmacology , Transcription Factors , Adenocarcinoma/metabolism , Animals , DNA Repair , Disease Models, Animal , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Female , Lung Neoplasms/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Metastasis , Neoplasm Transplantation , Phenotype , Transplantation, Heterologous , Xeroderma Pigmentosum Group D ProteinABSTRACT
We report the first case of 90Y-conjugated monoclonal antibody (MoAb) administration for human radioimmunotherapy. Ten mCi 90Y-labeled antiidiotype (anti-Id) MoAb were administered to a patient with B-cell lymphoma whose tumor successfully imaged with 111In-labeled anti-Id MoAb. No significant toxicities were observed. More than 2 g of unlabeled anti-Id MoAb were administered while clearing the circulating IgM idiotype prior to administration of the 90Y-MoAb. Transient partial regression of disease was observed. Serial fine needle aspirations of a malignant lymph node documented in vivo anti-Id penetration into a site that did not image by radioimmunoscintigraphy. The radiosensitivity of B-cell lymphoma, the tumor specificity of anti-Id, the antitumor activity of anti-Id alone, and the safe administration of 10 mCi 90Y-labeled anti-Id MoAb in this report suggest further investigation of this radioimmunoconjugate for therapy of B-cell lymphoma is warranted.
