4-(3-(2-nitro-1-imidazolyl)-propylamino)-7-chloroquinoline-hydrochloride and Neoplasms

Solid tumours contain regions of very low oxygen concentrations that are said to be hypoxic. Hypoxia is a natural phenotype of solid tumours resulting from an imperfect vascular network. There are a number of consequences associated with tumour hypoxia including: resistance to ionising radiation, resistance to chemotherapy and the magnification of mutated p53. In addition tissue hypoxia has been regarded as a key factor for tumour aggressiveness and metastasis by activation of signal transduction pathways and gene regulatory mechanisms. It is clear that hypoxia in solid tumours promotes a strong oncogenic phenotype and is a phenomenon that occurs in all solid tumours. As such this provides a significant target for drug discovery particularly for tumour-targeting agents. A range of chemical classes (N-oxides, quinones, nitro-aromatics) have been explored as bioreductive agents that target tumour hypoxia. The most advanced agent, tirapazamine, is in phase III clinical trials in combination with cis-platin. The aim of this review is to give a brief overview of the current molecules and strategies being explored for targeting tumour hypoxia.

Topics: Anthraquinones; Antineoplastic Agents; Aziridines; Benzoquinones; Cell Hypoxia; Clinical Trials, Phase III as Topic; Drug Screening Assays, Antitumor; Humans; Imidazoles; Indolequinones; Neoplasms; Prodrugs; Quinolines; Radiation-Sensitizing Agents; Tirapazamine; Triazines

The development of weak DNA-intercalating bioreductive compounds is a new strategy to ensure DNA affinity high enough to produce toxicity yet low enough to permit efficient extravascular diffusion and penetration to hypoxic tumor tissue, as has been exemplified by the lead compound 4-[3-(2-nitro-1-imidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1, NSC 709257). Indeed, because of its weak DNA-binding, NLCQ-1 demonstrates significant hypoxic selectivity in several rodent and human tumor cell lines that can be increased up to 388-fold with 4.5 h exposure. In vitro reduction studies suggest that cytochrome P450 and b(5) reductases play a significant role in NLCQ-1 bioreductive activation. NLCQ-1 synergistically enhances the effect of radiation against hypoxic cells in vitro and murine tumors in vivo and optimizes the effect of radioimmunotherapy in human xenografts. Importantly, NLCQ-1 substantially enhances, in a schedule-dependent manner, the antitumor effect of alkylating agents, as well as 5-fluorouracil and paclitaxel against murine tumors and human xenografts, without a concomitant enhancement in bone marrow or hypoxia-dependent retinal toxicity. In addition, NLCQ-1 exhibits good stability in human plasma and favorable pharmacokinetics in mice. The synthesis of NLCQ-1 has been successfully scaled-up and its excellent recovery from biological fluids has been established. Because of these results and the fact that NLCQ-1 compares favorably with the frontrunner, bioreductive compound tirapazamine, NLCQ-1 is about to enter a Phase I clinical trial.

Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Cell Line, Tumor; Drug Synergism; Humans; Imidazoles; Intercalating Agents; Neoplasms; Quinolines; Radioimmunotherapy

Bioreductive drugs can cause retinal toxicity, mediated by extensive apoptosis in the outer retina of rodents and monkeys. In the present study, we have investigated whether or not the novel and promising hypoxia-selective cytotoxin 4-[3-(2-nitro-1-imidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1, NSC 709257) can cause hypoxia-dependent retinal toxicity in BALB/c mice alone or in combination with cyclophosphamide (CPM), one of the anti-cancer agents that acts synergistically with NLCQ-1 against mouse tumours and human xenografts. The bioreductive agent tirapazamine (TPZ) was included for comparison purposes. Retinal damage was quantified by morphometric analysis of histological sections following IP treatment of female BALB/c mice. No retinal toxicity was observed with 10 or 22 mg/kg of NLCQ-1 or 23 mg/kg TPZ alone, whereas statistically significant retinal toxicity was observed with the higher TPZ dose of 52 mg/kg (p < 0.001). Thus, a normalized photoreceptor layer thickness (NPT) value of 0.50 ± 0.04, 0.48 ± 0.03 and 0.33 ± 0.06 was determined for untreated, NLCQ-1 and TPZ-treated mice at the highest dose, respectively. Marginal retinal toxicity was observed with the lower dose of TPZ in combination with CPM.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Cytotoxins; Dose-Response Relationship, Drug; Drug Synergism; Female; Humans; Hypoxia; Imidazoles; Mice; Mice, Inbred BALB C; Neoplasms; Quinolines; Retina; Tirapazamine; Triazines

Combined radioimmunotherapy (RAIT) and hypoxic cytotoxin therapy (SR4233 or NLCQ-1) have been evaluated with both modalities administered on the same day with only moderate improvement compared with the effects of RAIT alone. In a series of studies using oxygen electrodes, immunohistochemistry and radiotracers, we have demonstrated that RAIT induces a prolonged state of hypoxia in most tumors, without affecting the pO(2) levels in normal tissues. Using serial microelectrode measurements through subcutaneous (s.c.) GW-39 human colonic xenografts, we established that the median pO(2) was unrelated to the initial size of the tumor, over a range of sizes from 1.0 to 4.0 cm. Fourteen days after mice were given a 240-microCi dose of (131)I-MN-14 anti-carcinoembryonic antigen immunoglobulin G, their median pO(2) declined from 26.1 +/- 9.6 mmHg to 9.8 +/- 3.9 mmHg (p < 0.001). Using the radiotracer (3)H-MISO that accumulates in hypoxic regions, uptake in GW-39, LoVo and LS174T s.c. human colonic tumors increased 3.0- to 4.2-fold from day 14 through day 28 post-RAIT, but uptake of (3)H-MISO in CALU-3 tumors remained unchanged after RAIT. Normal tissue (liver, kidney, lung) uptake of (3)H-MISO did not exhibit significant changes. The increase in tumor hypoxia was also demonstrated visually using anti-PIMO staining of tumor sections. We postulated that sequential delivery of the 2 therapeutic agents, with the hypoxic cytotoxin given 2 weeks after RAIT when tumor pO(2) levels were at their nadir, would improve the therapeutic response above either modality alone or above the 2 agents delivered on the same day. Tumor growth was compared in mice given either RAIT or cytotoxin alone, the combined treatment on the same day or with the cytotoxin delivered 14 days after RAIT. Tumor size on day 35 for RAIT-treated and SR4233-treated GW-39 were 3.56 +/- 0.40 and 7.98 +/- 2.50 cm(3). When RAIT + SR4233 were delivered on the same day, tumor size dropped to 2.78 +/- 0.80 cm(3). If RAIT was given on day 0 and SR4233 on day 14, size further declined further to 1.74 +/- 0.32 cm(3) (p < 0.05 compared with same day delivery). For LS174T, tumor size on day 28 for RAIT-treated and SR4233-treated tumors were 1.14 +/- 0.36 cm(3) and 3.65 +/- 0.78 cm(3), respectively. When RAIT + SR4233 were delivered on the same day, size was 0.51 +/- 0.174 cm(3). If RAIT was dosed on day 0 and SR4233 was given on day 14, tumor size was 0.13 +/- 0.07 cm(3) (p < 0.05). Similar results were obtained for L

Topics: Animals; Antineoplastic Agents; Carcinoembryonic Antigen; Cell Hypoxia; Combined Modality Therapy; Cytotoxins; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hypoxia; Imidazoles; Immunoglobulin G; Mice; Mice, Nude; Microelectrodes; Neoplasm Transplantation; Neoplasms; Oxygen; Quinolines; Radiation-Sensitizing Agents; Radioimmunotherapy; Time Factors; Tirapazamine; Triazines; Tumor Cells, Cultured

A novel weakly DNA-intercalative bioreductive compound. 4-[3-(2-nitro-1-imidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1). has been synthesized and studied as a hypoxia-selective cytotoxin in vitro. NLCQ-1, which shares a similar structure with the DNA-intercalative antimalarial drug chloroquine, bound more strongly to DNA than the nonchlorinated analog NLQ-1 (4-[3-(2-nitro-1-imidazolyl)propylamino]-quinaldine hydrochloride). Thus, NLCQ-1 exhibited a C50 [concentration for 50% displacement of the ethidium bromide (EB) from a DNA-EB complex] of 44 microM, whereas a C50 value could not be reached for NLQ-1 up to 225 microM. NLCQ-1 demonstrated significant hypoxic selectivity in several rodent (V79, EMT6, SCCVII) or human (A549, OVCAR-3) tumor cell lines. Its potency as a hypoxic cytotoxin (expressed as the product of exposure time and concentration for 50% survival) ranged between 10 and 136 microM x h, for the cell lines tested, at 30 microM input concentration. Because uptake in all cell lines was similar, the differences in potency may reflect differences in the enzymatic profile or damage repair processes among the cell lines. In addition, however, the most striking feature of NLCQ-1 was that hypoxic selectivity increased with exposure time, a common feature normally found in only bis-bioreductive agents carrying two moieties with different redox potentials. Thus, hypoxic selectivity of NLCQ-1 in V79 cells at 50% survival was increased from fivefold up to 388-fold by increasing exposure time from 1 to 4.5 h, as the result of a concomitant increase and decrease in its hypoxic and aerobic potency, respectively, over time. Because the nonchlorinated analog NLQ-1 did not demonstrate similar behavior, we hypothesized that the C-7 chlorine of NLCQ-1 might play a significant role in this phenomenon.

Topics: Aminoquinolines; Animals; Antineoplastic Agents; Cell Survival; Chloroquine; Chromatography, Thin Layer; Cytotoxins; Dose-Response Relationship, Drug; Humans; Hypoxia; Imidazoles; Inhibitory Concentration 50; Models, Chemical; Neoplasms; Quinolines; Rats; Time Factors; Tumor Cells, Cultured