High uptake of RSU 1069 and its analogues melanotic melanomas.

RSU 1069 and RSU 1164 are electron affinic agents that contain a nitro group together with a weakly basic alkylating aziridine moiety, and they represent lead compounds in the development of dual-function, bioreductive, hypoxic cell radiosensitizers. We studied the pharmacokinetics of these drugs in mice carrying KHT sarcoma. Lewis lung carcinoma, and B16 melanoma.

Potentiation of the anti-tumour effect of melphalan by the vasoactive agent, hydralazine.

The vaso-active drug hydralazine causes a considerable increase in the cytotoxic effect of melphalan towards the KHT tumour in mice. The enhancement in response, measured as the concentration of melphalan required to achieve a given tumour response, is 3.0 and 2.

Dual-function radiation sensitizers and bioreductive drugs: factors affecting cellular uptake and sensitizing efficiency in analogues of RSU 1069.

Alkyl aziridine analogues of the hypoxic cell radiosensitizer RSU 1069 have been synthesized and one of these, RB 7040, containing the tetramethyl substituted aziridine, is a more efficient sensitizer in vitro than RSU 1069 (Ahmed et al., 1986). The extent to which variation in drug uptake can influence the sensitizing efficiency of RSU 1069 and its analogues has been investigated by determining the cellular uptake of these weakly basic sensitizers as a function of the pH of the extracellular medium (pHe) over the range 5.

Radiosensitization by the 2,4-dinitro-5-aziridinyl benzamide CB 1954: a structure/activity study.

CB 1954 (2,4-dinitro-5-aziridinyl benzamide) is a radiosensitizer which is up to 10 times more efficient in vitro than would be predicted on the basis of its electron affinity. In order to determine the contribution of the various functional groups comprising the molecule to overall sensitizing efficiency, nine structural analogues have been studied. The redox potential, E7(1), and sensitizing efficiency, C1.

Mechanism of action of some bioreducible 2-nitroimidazoles: comparison of in vitro cytotoxicity and ability to induce DNA strand breakage.

The interaction of a series of nitroimidazole-aziridine radiosensitisers, as parent or radiation-reduced species, with plasmid DNA in aqueous solution at pH7 results in strand breakage. The efficiency of strand breakage substantially increases on reduction of the nitroimidazole analogues. The rate of production of strand breaks decreases on interaction with both parent and reduced nitroimidazole analogues as the aziridine moiety is deactivated through alkyl-substitution.

A comparison of adriamycin and mAMSA. II. Studies with V79 and human tumour multicellular spheroids.

Multicellular spheroids were used to compare the two chemotherapeutic agents adriamycin (ADM) and 4'[(9-acridinyl)-amino] methanesulphon-m-anisidide (mAMSA). Chinese hamster cells, V79 379A, a human small cell lung carcinoma, designated ME/MAR, and a human melanoma xenograft, HX117, were grown as spheroids (200 or 400 micron in diameter) and treated with either drug for 1 h, at 37 degrees C, in air. Cytotoxicity was assayed using both cell survival and growth delay.

Chemosensitization by monofunctional alkylating agents.

The chemosensitizing ability of model monofunctional alkylating agents with known DNA base alkylating characteristics, that is, methylmethanesulphonate (MMS), ethyl methanesulphonate (EMS) and N-methyl-N-nitrosoguanidine (MNNG) have been investigated. Whereas the alkyl sulphonates chemosensitize V79 cells to cisplatin and melphalan, MNNG does not. The dose response curves show shoulder removal.

Induction of hypoxia in normal and malignant tissues by changing the oxygen affinity of hemoglobin--implications for therapy.

The drug BW12C, which increases the oxygen affinity of hemoglobin, reduces oxygen availability to tissues. This results in protection against radiation damage to the hemopoietic system and epidermal Langerhans cells in CBA mice. The drug also protects against beta-irradiation damage in pig epidermis.

The radiosensitizing and toxic effects of RSU-1069 on hypoxic cells in a murine tumor.

RSU-1069 is one of a group of compounds of particular interest in radiobiology, since it combines the nitroimidazole ring with a side chain bearing a monofunctional alkylating agent. This compound has been shown to be a potent radiosensitizer both in vitro and in vivo. Furthermore, it has recently been shown to be an effective hypoxic cell cytotoxin in vitro.

Studies on the mechanisms of the radiosensitizing and cytotoxic properties of RSU-1069 and its analogues.

RSU 1069 is a substantially more efficient sensitizer than misonidazole when hypoxic Chinese hamster V79 cells are irradiated in vitro at room temperature; such that for 0.5 mmol dm-3 sensitizer an ER of 3.0 is obtained for RSU 1069 whereas an ER of only 1.

Analogues of RSU-1069: radiosensitization and toxicity in vitro and in vivo.

A series of nitroimidazoles containing aziridine and alkyl-substituted aziridine functions has been synthesized. The 2-nitroimidazole compounds examined all show greater radiosensitizing efficiency in vitro than misonidazole. The 4- and 5-nitroimidazole analogues are also more efficient than equivalent compounds which do not contain the alkylating aziridine moiety.

The differential cytotoxicity of RSU 1069: cell survival studies indicating interaction with DNA as a possible mode of action.

The hypoxic cell radiosensitizer RSU 1069 (1-(2-nitro-1-imidazolyl)-3-(1-aziridinyl)-2-propanol) shows, on a concentration basis, a 100-fold greater toxicity towards hypoxic relative to aerobic cells. This toxicity is substantially greater than that of misonidazole, a compound of similar electron affinity. Reductive processes are important for hypoxic toxicity; this is demonstrated by the fact that misonidazole, in excess, can protect against the hypoxic but not aerobic toxicity of RSU 1069.

The interaction between radiation and complexes of cis-Pt(II) and Rh(II): studies at the molecular and cellular level.

A range of Rh(II) carboxylates and cis-Pt(II) complexes have been examined for their ability to increase the radiation sensitivity of aerobic and hypoxic V79 cells in vitro. The transition metal complexes sensitize in both air and nitrogen, with the greater effect generally occurring in nitrogen. The cis-Pt(II) complexes only show small levels of sensitization with dose modification factors (DMFs) of no more than 1.

Radiosensitizers of hypoxic mammalian cells. 1-(Hydroxyaminoalkyl)-substituted nitroimidazoles.

A series of novel 1-(hydroxyaminoalkyl)-substituted nitroimidazoles has been synthesized as potential radiosensitizers for hypoxic mammalian cells. These compounds were synthesized via N-(hydroxyalkyl)phthalimide nitroimidazole intermediates which, on reaction with hydrazine hydrate, yielded the corresponding amines. The intermediates were prepared by reacting the epoxide derived from nitroimidazole with phthalimide and/or the epoxide derived from phthalimide with the nitroimidazole.

Thiol reactive nitroimidazoles: radiosensitization studies in vitro and in vivo.

Using Chinese hamster V79 cells in vitro a study has been made of the radiosensitizing properties of 4- or 5-nitroimidazoles substituted in the 2, 5 or 4 position with various halo, sulphur ether, sulphonamide, sulphonate, ether or nitro groups. Values of E17 (the one-electron reduction potential measured versus the normal hydrogen electrode at pH7) vary in the range -178 to -565 mV. All the compounds, with one exception, are more efficient radiosensitizers than would be predicted from their redox potentials, and the factor, C1.

RSU 1069, a 2-nitroimidazole containing an alkylating group: high efficiency as a radio- and chemosensitizer in vitro and in vivo.

Electron affinity as measured by the one-electron reduction potentian, E7(1), is the major factor influencing radiosensitizing efficiency in vitro. RSU 1069 has an electron affinity (E7(1) = 398 mV) similar to misonidazole; however, the ability of this compound to sensitize hypoxic cells is considerably greater in vitro than that of misonidazole, e.g.

Chemopotentiation by CB 1954: the importance of postincubations and the possible involvement of poly(ADP-ribosylation).

CB 1954 potentiates the cytotoxic action of the bifunctional alkylating agent melphalan (L-PAM). In vitro, this potentiation does not require the preincubation in hypoxia normally needed for other nitroaromatic compounds such as misonidazole. Chemopotentiation is observed when cells are held in CB 1954 in air after treatment with L-PAM.

Radiosensitization of mammalian cells by transition metal complexes containing nitroimidazole ligands.

Various transition metal complexes containing nitroimidazoles as ligands have been shown to act as radiosensitizers of hypoxic cells in vitro. Sensitization by cis-Pt(II)Cl2 (nitroimidazole)2 complexes is no greater than that which can be demonstrated by the free nitroimidazole ligand alone. These results differ from those previously described for the compound FLAP where an ER of 2.

The radiation response of V79 and human tumour multicellular spheroids--cell survival and growth delay studies.

Chinese hamster cells (V79 379A) cells from a human small cell carcinoma of the lung (ME/MAR) and two xenografted human melanomas (HX117 and HX118) have been grown as multicellular spheroids in vitro. The radiation response of these four cell types has been compared when grown as spheroids (200 or 400 micron in diameter) and as single cells from disaggregated spheroids. The radiation sensitivity of the three human lines irradiated as single cells in air, is similar.

Radiation sensitization and chemopotentiation: RSU 1069, a compound more efficient than misonidazole in vitro and in vivo.

Electron affinity as measured by the one-electron reduction potential, E17, is the major factor influencing radiosensitizing efficiency in vitro. RSU 1069 has an electron affinity (E17 = -398 mV) similar to misonidazole; however, the ability of this compound to sensitize hypoxic cells is considerably greater than that of misonidazole, e.g.

Subharmonic emission as an indicator of ultrasonically-induced biological damage.

This paper describes work in which subharmonic emissions from ultrasonically irradiated biological samples are integrated over time, and the resultant signal (which is believed to be indicative of cavitation activity) is found to correlate well with the extent of cellular damage. Specifically, three studies have been carried out, in which the subharmonic energy emitted from suspension cultures of V79 cells is integrated during exposure to 1 MHz ultrasound. The effect of raised ambient pressure and sample rotation speed on the occurrence of cavitation, and of cavitation related cell death, have been investigated.

Radiosensitization in vivo: a study with an homologous series of 2-nitroimidazoles.

An homologous series of 1-(omega-morpholino)alkyl-2-nitroimidazoles, previously reported to be more efficient hypoxic cell radiosensitizers than misonidazole (MIS) in vitro, were evaluated in vivo using the murine Lewis Lung carcinoma. When given i.p.

Protection against misonidazole-induced neuropathy in rats: a biochemical assessment.

A biochemical method for assessing the chemically induced neurotoxicity of misonidazole (MISO) in the rat has been used to assess whether the concurrent administration of thiamine, thiamine pyrophosphate (TPP) or vitamin E (Vit.E) could afford protection against the neurotoxic side effects of the drug. The tissues analysed were distal sections of the sciatic/posterior tibial nerve (SPTN), trigeminal ganglia and cerebellum.