A Pt(IV)-based mononitro-naphthalimide conjugate with minimized side-effects targeting DNA damage response via a dual-DNA-damage approach to overcome cisplatin resistance.

Platinum(Pt)(II) drugs and new Pt(IV) agents behave the dysregulation of apoptosis as the result of DNA damage repair and thus, are less effective in the treatment of resistant tumors. Herein, mononitro-naphthalimide Pt(IV) complex 10b with minimized side-effects was reported targeting DNA damage response via a dual-DNA-damage approach to overcome cisplatin resistance. 10b displayed remarkably evaluated antitumor (70.10%) activities in vivo compared to that of cisplatin (52.88%). The highest fold increase (FI) (5.08) for A549cisR cells and the lowest (0.72) for A549 indicated 10b preferentially accumulated in resistant cell lines. The possible molecular mechanism indicates that 10b targets resistant cells in a totally different way from the existing Pt drugs. The cell accumulation and the Pt levels in genomic DNA from 10b is almost 5 folds higher than that of cisplatin and oxaliplatin, indicating the naphthalimide moiety in 10b exhibits preferentially DNA damage. Using 5'-dGMP as a DNA model, the DNA-binding properties of 10b (1 mM) with 5'-dGMP (3 mM) in the presence of ascorbic acid (5 mM) deduced that 10b was generated by the combination of cisplatin with 5'-dGMP after reduction by ascorbic acid. Moreover, 10b promoted the expression of p53 gene and protein more effectively than cisplatin, leading to the increased anticancer activity. The up-regulated γH2A.X and down-regulated RAD51 indicates that 10b not only induced severe DNA damage but also inhibited the DNA damage repair, thus resulting in its higher cytotoxicity in comparison to that of cisplatin. Their preferential accumulation in cancer cells (SMMC-7721) compared to the matched normal cells (HL-7702 cells) demonstrated that they were potentially safe for clinical therapeutic use. In addition, the higher therapeutic indices of 10b for 4T1 cells in vivo indicated that naphthalimide-Pt(IV) conjugates behaved a vital function in the treatment of breast cancer. For the first time, our study implies a significant strategy for Pt drugs to treat resistance cancer targeting DNA damage repair via dual DNA damage mechanism in a totally new field.

Phase I trial of UNBS5162, a novel naphthalimide in patients with advanced solid tumors or lymphoma.

OBJECTIVES: UNBS5162 is a novel naphthalimide that binds to DNA by intercalation and suppresses CXCL chemokine elaboration. A Phase I study of UNBS5162 was conducted to establish pharmacokinetics (PK), maximum tolerated dose (MTD), dose-limiting toxicity, safety and anti-tumor activity in patients with advanced solid tumors or lymphoma. METHODS: UNBS5162 was administered in a 3 + 3 dose escalation scheme by intravenous infusion over 1 h weekly for 3 weeks of a 4-week cycle. Safety, serial serum PK and tolerability were captured throughout the study. Response Evaluation Criteria in Solid Tumors was utilized every 2 cycles to assess for anti-tumor response. RESULTS: Twenty-four patients with metastatic carcinoma and 1 patient with lymphoma were treated at eight dose levels (18-234 mg/m(2)). All patients were evaluable for tolerability and toxicity. Grade 3 toxicities include nausea (n = 1), fatigue (n = 1) and anorexia (n = 1). Prolongation of QTc [Hodges] was observed in 6 cases (Gr 1 = 2; Gr 2 = 2; Gr 3 = 2). C(max) and area under the curve increased linearly with dose with a t(1/2) of 30-60 min. 16 patients completed 2 cycles of therapy, all with pharmacodynamics at 8 weeks. CONCLUSIONS: The MTD or dose-limiting toxicity for UNBS5162 was not reached due to the magnitude of QTc prolongation at the highest dose of 234 mg/m(2)/week that led to study termination.

Amonafide: a future in treatment of resistant and secondary acute myeloid leukemia?

Development of the novel topoisomerase II inhibitor, amonafide, began almost 40 years ago. The drug was selected for further investigation owing to evidence of marked antineoplastic efficacy in preclinical models of cancer. When its usefulness in the treatment of various solid malignancies proved limited, focus was shifted to establishing its use as an antileukemic agent, specifically against secondary and treatment-associated acute myeloid leukemia (AML). While Phase I and II studies gave rise to hopes that amonafide might hold the key to treating older patients, including those with multidrug resistant, cytogenetically unfavorable secondary and treatment-associated AML, when used in combination with cytarabine, it failed to demonstrate a survival advantage over standard-of-care therapy in randomized studies. This article will outline the development of amonafide from the laboratory to the bedside and discuss the potential place that this agent has in the current management of AML.

Methoxyethylamino-numonafide is an efficacious and minimally toxic amonafide derivative in murine models of human cancer.

Amonafide is a DNA intercalator in clinical development for the treatment of cancer. The drug has a 5-position amine that is variably acetylated to form a toxic metabolite in humans, increasing adverse effects and complicating the dosing of amonafide. Numonafides, 6-amino derivatives of amonafide that avoid the toxic acetylation, also show in vitro anticancer activity, as we have previously described. Here, we report the in vitro and in vivo activities of two numonafides, 6-methoxyethylamino-numonafide (MEAN) and 6-amino-numonafide (AN) with comparisons to amonafide. The in vitro potencies and cellular anticancer mechanisms are similar for the two numonafides and amonafide. Results from several mouse models of human cancer demonstrate that AN and MEAN require slightly higher doses than amonafide for equal efficacy in short-term dosing models, but the same dose of all three compounds in long-term dosing models are equally efficacious. MEAN is tolerated much better than amonafide and AN at equally efficacious doses based on weight change, activity, stool consistency, and dose tolerance with survival as the end point. The studies presented here demonstrate that MEAN is much less toxic than amonafide or AN in mouse models of human liver and gastric cancers while being equally efficacious in vivo and inhibiting cancer cells through similar mechanisms. These findings demonstrate that numonafides can be less toxic than amonafide and support further preclinical development and novel anticancer agents or as replacements or amonafide.

Phase I trials of amonafide as monotherapy and in combination with cytarabine in patients with poor-risk acute myeloid leukemia.

Amonafide-l-malate (amonafide) is a unique DNA intercalator that maintains activity in the presence of MDR mechanisms, a frequent cause of treatment-failure in secondary AML. 43 patients with relapsed/refractory or secondary AML or CML blast crisis were enrolled into two phase I dose-escalation studies investigating amonafide as monotherapy or in combination with cytarabine. 3/17 patients in the monotherapy trial and 10/26 patients in the combination trial achieved a complete remission. Between both trials responses occurred in 9/20 patients with secondary AML. Both trials demonstrated an acceptable safety profile and significant antileukemic activity in patients with poor-risk AML, especially those with secondary AML.