azonafide and Neoplasms

Naphthalimides, a class of compounds which bind to DNA by intercalation, have shown high anti-cancer activity against a variety of murine and more notably human cancer cell lines. Azonafide derivatives are also potential anti-tumor agents which are structurally related to the naphthalimides. Derivatives of azonafide have shown enhanced activity against various cancer models, especially leukemias, breast cancer and melanoma. Naphthalimides in general and amonafide in particular, are most probably the agents which have been involved in the greatest number of clinical trials without ever acceding to the market because of dose-limiting toxicity. This statement also reflects the immense interest that oncologists have paid to this class of compounds with respect to their anti-cancer potential. While the first generation of naphthalimides were mainly topoisomerse II poisons, some new compounds display novel mechanism of action. In contrast to the most widely used topo II poisons, including etoposide, adriamycin and their analogues, which often induce multi-drug resistance, several naphthalimide-related compounds have been reported not to be affected by this phenomenon. Multi-disciplinary approaches including medicinal chemistry, early toxicology and DMPK, in vivo activity assessment in diverse preclinical models and in-depth mechanism of action deciphering, along with the lessons learnt from previous and currently ongoing clinical trials, have resulted in the generation of a number of novel promising naphthalimide derivatives. It is thus reasonable to expect that members of this class of compounds will reach the oncology market in the near future.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Design; Humans; Inhibitory Concentration 50; Molecular Structure; Naphthalimides; Neoplasms; Structure-Activity Relationship

The azonafides are a series of anthracene-based DNA intercalators which inhibit tumor cell growth in vitro at low nanomolar concentrations and are not affected by the multidrug resistance phenomenon (MDR). Prior studies have described antitumor efficacy in murine tumor models including L-1210 and P-388 leukemias, and B-16 melanoma. The current results extend these cell line observations to human tumors tested in the NCI panel of 56 cell lines, in freshly isolated tumors tested in colony-forming assays in soft agar and in several animal models. In the NCI panel, the overall mean 50% cell kill (LC50) for the unsubstituted azonafide, AMP-1, was 10(-5.53) M, with some selectivity noted in melanomas (10(-6.22) M). The mean LC50 for the 6-ethoxy substituted analog, AMP-53, was 10(-5.53) M, with some selectivity found in non-small cell lung cancer (10(-5.91)) and renal cell carcinoma (10(-5.84)). In freshly isolated human tumors tested in soft agar, there was marked activity (mean IC50 in microg/ml) for AMP-53 in four cell types: breast cancer (0.09), lung cancer (0.06), renal cell carcinomas (0.06) and multiple myeloma (0.03). These effects were superior to doxorubicin and to several other azonafides, including AMP-1, AMP-104 and the 6-hydroxyethoxy derivative, AMP-115. Compound AMP-1 was shown to be superior to amonafide in the mammary 16C breast cancer model in B6CF31 mice, but it had little activity in Colon-38 nor in M5076 ovarian sarcomas in vivo. Nine azonafides were evaluated in the Lewis lung cancer model in C57/bl mice, but only AMP-53 demonstrated significant efficacy with a treated/control x 100% (T/C) value of 30%. Because AMP-53 demonstrated the greatest breadth of activity, it was then evaluated in several human tumor cell lines growing in mice with severe combined immunodeficiency disease (SCID). Only three tumors were sensitive (T/C<42%), including HL-60 leukemia (T/C=39%), MCF-7 breast cancer (T/C=39%) and A549 non-small cell lung cancer (T/C=37%). Overall, these results demonstrate that the 6-ethoxy substituted azonafide, AMP-53, has consistent (in vitro and in vivo) experimental antitumor activity in human breast and lung cancer, and could be considered for clinical testing in patients with MDR tumors.

Topics: Adenine; Animals; Antineoplastic Agents; Colony-Forming Units Assay; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Humans; Imides; Intercalating Agents; Isoquinolines; Male; Mice; Mice, Inbred C57BL; Mice, Nude; Naphthalimides; Neoplasms; Organophosphonates; Tumor Cells, Cultured; Tumor Stem Cell Assay