apaziquone and Carcinoma--Non-Small-Cell-Lung

EO9 (Apaziquone) is a bioreductive drug that has a chequered history. It underwent clinical trial but failed to show activity in phase II clinical trials when administered i.v. Poor drug delivery to tumours caused by a combination of rapid pharmacokinetic elimination and poor penetration through avascular tissue were the major factors responsible for EO9's poor efficacy. Based upon an understanding of why EO9 failed, a further clinical trial against patients with superficial transitional cell carcinoma of the bladder was conducted. The rationale for this was that intravesical administration directly into the bladder would circumvent the drug delivery problem, and any drug reaching the blood supply would be rapidly cleared thereby reducing the risk of systemic exposure. EO9 was well tolerated, and clinical activity against marker lesions was recorded in both phase I and II clinical trials. This article charts the pharmacological history of EO9 and discusses the potential implications that 'the EO9 story' has for the development of other loco-regional therapies.

Topics: Administration, Intravesical; Animals; Antineoplastic Agents; Area Under Curve; Aziridines; Carcinoma, Non-Small-Cell Lung; Carcinoma, Transitional Cell; Disease Models, Animal; Drug Delivery Systems; Humans; Immunohistochemistry; Indolequinones; Lung Neoplasms; Treatment Failure; Urinary Bladder; Urinary Bladder Neoplasms

In a multicentre randomized trial of the EORTC-ECSG, we have treated 38 chemotherapy naïve patients with advanced non-small-cell lung cancer (NSCLC) with EO9, a novel bio-reductive alkylating indoloquinone. The drug was given at two different dose schedules by a single bolus i.v. injection: arm A 12 mg/m2 weekly and arm B 22 mg/m2 every three weeks. All together 185 courses were administered (145 in arm A and 40 in arm B). The major toxicity was reversible proteinuria more frequently occurring in the three-weekly schedule (arm A 34.5% vs. arm B 62.5%). Creatinine elevation, fluid retention and pericardial or pleural effusion were also recorded in a limited number of patients. Other common toxicities more frequent in the three-weekly administration were asthenia (21% vs. 35% of cycles), nausea (15% vs. 27.5% of cycles) and vomiting (5% vs. 17.5% of cycles). Toxicities were mainly of grade I and II. No responses have been observed. Five patients (26%) on arm A and eight (53%) on arm B experienced stable disease. These doses and schedules of EO9 do not yield activity in NSCLC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Aziridines; Carcinoma, Non-Small-Cell Lung; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Indolequinones; Indoles; Injections, Intravenous; Lung Neoplasms; Male; Middle Aged; Survival Rate; Treatment Outcome

A series of regioisomeric analogues of 3-hydroxymethyl-5-aziridinyl-1-methyl-2-[1H-indole-4,7-dione]prop-2-en-1 -ol (EO9, NSC 382459) with the hydroxymethyl and hydroxypropenyl substituents situated at either the 2- or the 3-position of the indole ring were synthesized. The compound lacking the 2-hydroxypropenyl substituent (31) had similar properties to EO9 under both aerobic and hypoxic conditions against V79 cells and was more potent against a human tumour cell line (A549) than EO9. It was reduced by human DT-diaphorase (DTD) at more than double the rate of EO9, thus implicating the importance of the enzyme activation step. Compound 16 (lacking the 3-hydroxymethyl substituent) was a better substrate for human DTD than EO9, yet exhibited lesser toxicity under both aerobic and hypoxic conditions. The toxicity generated by 16 was attributed to the 5-aziridinyl moiety and suggests a greater contribution from the 3-substituent over the 2-substituent. The toxicity of EO9 was attributed to a combination of the aziridinyl group and the leaving group properties of the 3-hydroxymethyl substituent. In general, compounds with a 5-methylaziridinyl moiety, such as EO8, exhibited substantially better hypoxia-selectivity due to much slower reduction by DTD (20-fold), thus reducing aerobic potency. All compounds had similar electron affinities, as indicated by their one-electron reduction potentials.

Topics: Aerobiosis; Animals; Antineoplastic Agents; Aziridines; Carcinoma, Non-Small-Cell Lung; Cell Hypoxia; Cell Line; Cricetinae; Cricetulus; Fibroblasts; Humans; Indolequinones; Indoles; Lung Neoplasms; NAD(P)H Dehydrogenase (Quinone); Stereoisomerism; Structure-Activity Relationship; Tumor Cells, Cultured

DT-diaphorase (DTD) is an important enzyme for the bioreductive activation of the new alkylating indoloquinone EO9. In preclinical studies, EO9 has shown selective anti-tumour activity against solid tumours and under hypoxic conditions. The levels of three reductive enzymes have been determined in three types of human solid tumours, together with corresponding normal tissues and normal liver. DTD enzyme activities were measured in tumour extracts using 2,6-dichlorophenolindophenol (DCPIP) and NADH as substrates; cytochrome P450 reductase or cytochrome b5 reductase activities were assessed with cytochrome c and NADPH or NADH respectively. DTD activity was highest in non-small-cell lung (NSCLC)-tumours (mean 123 nmol DCPIP min-1 mg-1), followed by colon carcinoma (mean 75 nmol min-1 mg-1) and squamous cell carcinoma of the head and neck (6-fold lower than NSCLC). DTD activity was very low in normal liver and normal lung (4-6 nmol min-1 mg-1), while the levels in normal colon mucosa or normal mucosa of the head and neck region were in the same range as the corresponding tumours. The levels of the two other reductive enzymes, cytochrome P450 reductase (CP450R) and cytochrome b5 reductase (Cb5R), were 5 to 25-fold lower than those of DTD in all the tissues, except for normal liver, in which DTD was 2 to 4-fold lower. The degree of variation found for DTD (range 4-250 nmol min-1 mg-1), was not observed for these enzymes (CP450R, 0.8-7.8 nmol cytochrome c min-1 mg-1; Cb5R, 3.5-27.6 nmol min-1 mg-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antineoplastic Agents; Aziridines; Carcinoma, Non-Small-Cell Lung; Colonic Neoplasms; Humans; Indolequinones; Indoles; Lung Neoplasms; NAD(P)H Dehydrogenase (Quinone); Neoplasms