Characterization of Batracylin-induced Renal and Bladder Toxicity in Rats

Abstract

Batracylin (NSC-320846) is a dual inhibitor of DNA topoisomerases I and II. Batracylin advanced as an anticancer agent to Phase I clinical trials where dose limiting hemorrhagic cystitis (bladder inflammation and bleeding) was observed. To further investigate batracylin’s mechanism of toxicity, studies were conducted in Fischer 344 rats. Once daily oral administration of 16 or 32 mg/kg batracylin to rats for 4 days caused overt toxicity. Abnormal clinical observations and adverse effects on clinical pathology, urinalysis, and histology indicated acute renal damage and urothelial damage and bone marrow dysfunction. Scanning electron microscopy revealed sloughing of the superficial and intermediate urothelial layers. DNA damage was evident in kidney and bone marrow as indicated by histone γ-H2AX immunofluorescence. After a single oral administration of 16 or 32 mg/kg, the majority of batracylin was converted to N-acetylbatracylin (NAB) with a half-life of 4–11 hr. mesna (Mesnex™), a drug known to reduce the incidence of hemorrhagic cystitis induced by ifosfamide or cyclophosphamide, was administered to rats prior to batracylin, but did not alleviate batacylin-induced bladder and renal toxicity. These findings suggest that batracylin results in DNA damage-based mechanisms of toxicity and not an acrolein-based mechanism of toxicity as occurs after ifosfamide or cyclophosphamide administration.

Comparative Metabolism of Batracylin (NSC 320846) and Nacetylbatracylin (NSC 611001) Using Human, Dog, and Rat Preparations In Vitro

“…A recent investigative toxicology study in rats [13] showed that oral administration of BAT resulted in dose-dependent renal and urothelial (urinary bladder) damage, with frank hematuria in some high-dose animals (it is likely that bladders were not specifically examined in the 1980s toxicology studies). Pharmacokinetic analysis confirmed that NAB was by far the predominant species in plasma, although low levels of BAT and hydroxyl-metabolites of NAB were detected.…”

“…While this effect likely arises from BAT interactions with topoisomerases [4], the consequences of direct covalent binding of “activated” BAT to DNA should be further explored. Results of this toxicology study [13] also argued against a cyclophosphamide-like mechanism of toxicity mediated by production of acrolein, since co-administration of the protective agent, MESNA, did not alleviate BAT-induced renal or bladder toxicity.…”

Discovery of Novel Topoisomerase II Inhibitors by Medicinal Chemistry Approaches

“…Guided by the tetracyclic indenoquinoline-derived ellipticine ( 86 ) and batracylin (BAT, NSC320846, 112 ), which have emerged as notable DNA intercalators with significant topo II inhibitory activities, Chen and co-workers developed a panel of tetracyclic indeno­[1,2- c ]­quinoline derivatives 113 via structural replacement of the tetracyclic backbone of 112 and subsequent oximation to the corresponding O -substituted oximes. Among them, 113a – c had the most potent antiproliferative activities toward A549 or HeLa cells, acting as DNA intercalating agents.…”

Topoisomerase 1B poisons: Over a half‐century of drug leads, clinical candidates, and serendipitous discoveries

“…Compound 47 is a dual Top1/Top2 poison that induces DNA breaks that persist longer than those induced by 1 or etoposide and induces γ‐H2AX formation . Unfortunately, 47 is highly insoluble and was toxic to dogs, mice, and especially rats, where it caused kidney and bladder damage, as rats metabolize it to a toxic N ‐acetyl analog . Thus, human clinical trials were indicated only for patients with a “slow acetylator” genotype.…”

“…266 Unfortunately, 47 is highly insoluble and was toxic to dogs, mice, and especially rats, where it caused kidney and bladder damage, as rats metabolize it to a toxic N-acetyl analog. 267 Thus, human clinical trials were indicated only F I G U R E 1 2 Luotonin A and synthetic luotonin derivatives for patients with a "slow acetylator" genotype. However, cystitis was still a considerable problem, and the low efficacy of the drug forced cessation of trials circa 2013.…”