apaziquone and Breast-Neoplasms

In a phase II trial, the activity of EO9, a new bioreductive alkylating agent, was assessed. EO9 was used as second-line chemotherapy in breast cancer patients and as first-line chemotherapy for patients with gastric, pancreatic and colorectal cancer. EO9 was given as a 5 min i.v. infusion at a weekly dose of 12 mg/m2. 92 patients were entered; 22 with breast cancer, 26 with colon cancer, 24 with pancreatic cancer and 20 with gastric cancer. In general, the drug was well tolerated with nausea and vomiting occurring in 26.42 and 13.3% of courses, respectively. Reversible proteinuria was the main toxicity occurring in 45% of courses. Antitumour activity was not observed. At this dose and schedule, EO9 is not an active drug in the type of tumour studied.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Aziridines; Breast Neoplasms; Colorectal Neoplasms; Digestive System Neoplasms; Female; Follow-Up Studies; Humans; Indolequinones; Indoles; Male; Middle Aged; Pancreatic Neoplasms; Proteinuria; Stomach Neoplasms

EO9 [3-hydroxy-5-aziridinyl-1-methyl-2(1H-indole-4,7-dione)-prop-beta-en- alpha-ol] was selected for clinical trial in Europe because of its preclinical profile but also because of its distinct mechanism of bioactivation. Several studies have shown that cells rich in DT-diaphorase may be particularly sensitive to EO9. The present study examined the relationship between DT-diaphorase activity and sensitivity to EO9 in a panel of cell lines largely derived from human and rodent leukaemias/lymphoma and solid tumours. A possible relationship between chemosensitivity and enzyme activity was demonstrated (correlation coefficient 0.796). A number of the human cell lines were established as xenografts in nude mice but, with the exception of HT29, DT-diaphorase specific activity was greatly reduced compared with the corresponding cell lines. These data suggest that in vitro studies of bioactivation of drugs by specific enzymes is unlikely to be relevant for the same tumour in vivo. Except for HCLO, all xenografts failed to respond to EO9 as a single dose. HT29 tumours in vivo had similar DT-diaphorase activity [359 nmol of 2,6-dichlorophenol-indophenol (DCPIP) reduced per min per mg of protein] to the cell line (337) but failed to respond to a single dose or daily dose schedule. A preliminary attempt to investigate an hourly dose schedule demonstrated a modest anti-tumour effect accompanied by enhanced toxicity. Attempts to optimise EO9 exposure parameters to potentiate activity in tumours with high DT-diaphorase activity are under way, but as yet the relevance of this particular enzyme for in vivo EO9 activity requires further investigation.

Topics: Animals; Antineoplastic Agents; Aziridines; Biotransformation; Breast Neoplasms; Cell Line; Cell Survival; Cricetinae; Cricetulus; Dihydrolipoamide Dehydrogenase; Humans; Indolequinones; Indoles; Mice; Mice, Nude; Neoplasms; Transplantation, Heterologous; Tumor Cells, Cultured

Twenty-three human tumour cell lines (lung, breast, and colon) and eight rodent cell lines were evaluated for their sensitivity to the quinone-based anticancer drug EO9 [3-hydroxymethyl-5-aziridinyl-1-methyl-2-(1H indole-4,7-dione)prop-beta-en-alpha-o1]. Sensitivity was compared with the intracellular levels of DT-diaphorase, and cell lines showing highest enzyme activity tended to be the most sensitive to EO9. The role of DT-diaphorase in determining drug sensitivity was confirmed by using the enzyme inhibitor dicoumarol, which protects cells containing high levels of DT-diaphorase from the cytotoxic action of EO9. Hypoxia increased the cytotoxicity of cells containing low but not high levels of DT-diaphorase, implying that both 1- and 2-electron reductive activation processes can be important for expression of EO9 toxicity. It is concluded that EO9 is a potentially useful agent in the enzyme directed approach to the use of bioreductive drugs in cancer therapy.

Topics: Animals; Antineoplastic Agents; Aziridines; Breast Neoplasms; Colonic Neoplasms; Cricetinae; Humans; Hypoxia; Indolequinones; Indoles; Lung Neoplasms; Mammary Neoplasms, Animal; NAD(P)H Dehydrogenase (Quinone); Oxygen; Tumor Cells, Cultured