ABSTRACT
PURPOSE: This study is to document the activity and acceptability for a new topical agent, A-007, in the treatment of cutaneous metastases from cancer. PATIENTS AND METHODS: This is a multicenter study involving 27 patients with inoperable skin lesions from histologically confirmed cancers of the breast and oral cavity, non-Hodgkin's lymphoma, Kaposi's sarcoma, and angiosarcoma that had failed radiotherapy or systemic treatment. A-007, as a 0.25% gel, was applied twice daily to the areas of cancer to be measured as well as applied to a healthy control area distant from the cancer areas. An untreated cancer area was also included and documented as a cancer control. RESULTS: The overall objected response rate with A-007 was 26%, with an additional 19% minimum response/stabilization of cancer. For patients with breast cancer, hormonal status did not have an impact on response. The median duration of response was 15 weeks (with one patient having a response for 3.5 years). Toxicities observed were itching, burning, and a rash, in 6 of the 27 patients. The skin toxicities were in the cancer-treated fields; none were observed in the A-007 control areas. All irritated areas cleared while continuing treatment, and the tumor lesions in the areas of itching also improved. CONCLUSION: A-007, as a 0.25% gel, is confirmed as an effective palliative treatment option for cutaneous metastases from cancers. Skin reactions were minimal, tolerated, and no cessation of treatment was required.
Subject(s)
Antineoplastic Agents/therapeutic use , Hydrazones/therapeutic use , Phenols/therapeutic use , Skin Neoplasms/drug therapy , Administration, Topical , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Female , Humans , Hydrazones/adverse effects , Hydrazones/pharmacokinetics , Male , Middle Aged , Multicenter Studies as Topic , Phenols/adverse effects , Phenols/pharmacokinetics , Skin Neoplasms/metabolism , Skin Neoplasms/secondaryABSTRACT
4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) has recently completed a phase I clinical trial in advanced cancer with minimal toxicity, and impressive objective responses were noted. A-007 possesses three moieties that appear to have an influence on its anticancer activities: diphenylmethane, hydrazone, and dinitrophenyl. The goals of this study were to modify A-007's chemical moieties with the ultimate goal of maximizing its anticancer activity through increased planarity and introduction of functional groups. Thirty-five phenylhydrazone analogues of A-007 were synthesized and evaluated in vitro in a human primary cancer explant assay. Anticancer activities for selected analogues were also assayed for activity vs established human/murine cell lines. One-hundred-eighty-six fresh human solid tumors were used to screen for anticancer activity. Selected analogues were assayed for therapeutic indices (vs GM-CFC from bone marrow) in preparation for preclinical studies. Several polyaryl phenylhydrazones demonstrated improved cytotoxic activities by factors of 10(2)-10(3) when compared with A-007. However, the polyaryl quinone moieties of the latter analogues introduced potential toxic properties (cardiac, hematological) that do not exist with A-007.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Hydrazones/chemical synthesis , Hydrazones/pharmacology , Phenols/chemical synthesis , Phenols/pharmacology , Animals , Cell Division/drug effects , Crystallography, X-Ray , Culture Techniques , Drug Design , Drug Screening Assays, Antitumor , Humans , Hydrogen Bonding , Indicators and Reagents , Mice , Stem Cells/drug effects , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
The structure of the anticancer agent 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone (A-007) has been modified through SAR and by incorporating barbituric acid, pyridine, quinoline, and alkylcarboxylic acids into A-007's moieties. Analogue anticancer activity and interacting with CD surface markers on a T-cell leukemia cell line were evaluated and the correlation between SAR and biological properties are discussed.
