Randomized clinical trial of mitomycin c as an adjunct to radiotherapy in head and neck cancer

Weissberg, Joseph B.; Son, Yung H.; Papac, Rose J.; Sasaki, Clarence T.; Fischer, Dennis; Lawrence, R. F.; Rockwell, Sara; Sartorelli, Alan C.; Fischer, James J.

doi:10.1016/0360-3016(89)90362-3

Cited by 186 publications

(41 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Based on these results, we hypothesized that AO could be excited by X-ray irradiation. Many anti-cancer drugs which show a radiation enhancement effect have been reported previously, and these include mitomycin C [42, 43], bleomycin [44, 45], doxorubicin [46], methotrexate [47], 5-fluorouracil and cisplatin [48, 49]. Although possible mechanisms of enhancement have been reported [50], the exact mechanism is still unclear.…”

Section: Discussionmentioning

confidence: 99%

Acridine Orange Excited by Low-Dose Radiation Has a Strong Cytocidal Effect on Mouse Osteosarcoma

Hashiguchi¹,

Kusuzaki²,

Murata³

et al. 2002

Oncology

View full text Add to dashboard Cite

The study was conducted to clarify the cytocidal effect of combination therapy consisting of administration of acridine orange (AO), which is a photosensitizer, and radiation therapy using in vitro and in vivo mouse osteosarcoma models. The results revealed that AO combined with low-dose X-ray irradiation of about 1–5 Gy had a strong cytocidal effect on the cultured mouse osteosarcoma cells regardless of their chemosensitivity, and that this combination therapy inhibited growth of the in vivo mouse osteosarcoma by induction of tumor necrosis. This effect was inhibited by L-histidine, but not by mannitol. These findings suggested that AO might be excited by X-rays and kill osteosarcoma cells through the release of singlet oxygen, which is toxic to living cells. This mechanism is similar to that of photodynamic therapy with AO.

show abstract

Section: Discussionmentioning

confidence: 99%

Acridine Orange Excited by Low-Dose Radiation Has a Strong Cytocidal Effect on Mouse Osteosarcoma

Hashiguchi¹,

Kusuzaki²,

Murata³

et al. 2002

Oncology

View full text Add to dashboard Cite

show abstract

“…If this were the case, it is possible that the tumour cell toxicity could be increased without changing the systemic toxicity or the systemic toxicity could be decreased without changing tumour cell toxicity, thereby increasing the therapeutic ratio. (Kim & Brown, 1993 (Weissberg et al, 1989) is an example of such a study. However, mitomycin C is toxic, not only to hypoxic, but also to aerobic cells, and there is often little or no differential toxicity between hypoxic and aerobic cells (Fracasso & Sartorelli, 1986;Stratford & Stephens, 1989).…”

Section: Mechanism Of Hypoxic Toxicity Of Sr 4233mentioning

confidence: 99%

SR 4233 (Tirapazamine): a new anticancer drug exploiting hypoxia in solid tumours

1993

Br J Cancer

338

219

View full text Add to dashboard Cite

SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide, WIN 59075, tirapazamine) is the lead compound in a new class of bioreductive anticancer drugs, the benzotriazine di-N-oxides. It is currently undergoing Phase I clinical testing. The preferential tumour cell killing of SR 4233 is a result of its high specific toxicity to cells at low oxygen tensions. Such hypoxic cells are a common feature of solid tumours, but not normal tissues, and are resistant to cancer therapies including radiation and some anticancer drugs. The killing of these tumour cells by SR 4233, particularly when given on multiple occasions, can increase total tumour cell killing by fractionated irradiation by several orders of magnitude without increasing toxicity to surrounding normal tissues. Topics covered in this review include the rationale for developing a hypoxic cytotoxic agent, the cytotoxicity of SR 4233 as a function of oxygen concentration, the mechanism of action of the drug and its intracellular target and the in vivo evidence that the drug may be useful as an adjunct both to radiotherapy and chemotherapy. Finally, the major unanswered questions on the drug are outlined.

show abstract

“…1 a natural product antibiotic with antitumor activity, has been used successfully to eradicate hypoxic tumor cells in head, neck, and cervix cancers in combination with ionizing radiation (1)(2)(3)(4). As a prodrug, MC can be chemically and enzymatically converted into a reactive species capable of alkylating a variety of nucleophilic molecules, including genomic DNA (5).…”

Section: Mitomycin C (Mc)mentioning

confidence: 99%

Nuclear Overexpression of NADH:Cytochromeb 5 Reductase Activity Increases the Cytotoxicity of Mitomycin C (MC) and the Total Number of MC-DNA Adducts in Chinese Hamster Ovary Cells

Holtz

Rockwell

Tomasz

et al. 2003

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

NADH:cytochrome b 5 reductase (FpD) is an enzyme capable of converting the prodrug mitomycin C (MC) into a DNA alkylating agent via reduction of its quininone moiety. In this study, Chinese hamster ovary (CHO) cells were transfected with a cDNA encoding rat FpD. Despite the demonstrated ability of this enzyme to reduce MC in vitro, a modest 5-fold level of overexpression of FpD activity in CHO cells did not increase the cytotoxicity of the drug over that seen with the parental cell line under either aerobic or hypoxic conditions. When the enzyme, which is predominantly localized in the mitochondria, was instead directed to the nucleus of cells by the fusion of the SV40 large T antigen nuclear localization signal sequence to the amino terminus of an FpD gene that lacked the membrane anchor domain, drug sensitivity was significantly enhanced at all concentrations of MC examined (2-10 M) under both aerobic and hypoxic conditions, with greater cell kill occurring under hypoxia. The marked increase in drug sensitivity under hypoxia at 10 M MC corresponded to a measurable increase in total MC-DNA adducts at the same concentration. The results indicate that the cytotoxicity of MC is modulated by the subcellular location of FpD, with greater cell kill occurring when bioactivation occurs in the proximity of its target, nuclear DNA.Mitomycin C (MC), 1 a natural product antibiotic with antitumor activity, has been used successfully to eradicate hypoxic tumor cells in head, neck, and cervix cancers in combination with ionizing radiation (1-4). As a prodrug, MC can be chemically and enzymatically converted into a reactive species capable of alkylating a variety of nucleophilic molecules, including genomic DNA (5). Specifically, the quinone moiety of MC is reduced to give unstable intermediates that are capable of further transformations to generate a reactive molecule with two electrophilic carbon centers (6). Both monofunctional and bifunctional adducts are formed between MC and DNA (7, 8).The variety of adducts formed between MC and DNA both in vitro and in drug-treated EMT6 cells have been extensively characterized (9 -13). The majority of these lesions are monofunctional alkylations occurring on the guanine-N(2) position. These lesions are considered to be less cytotoxic than the covalent bifunctional cross-link that forms exclusively in the 5Ј-CpG-3Ј sequence between the N-2 amino groups of two guanines in complementary strands of the minor groove. This interstrand MC-DNA cross-link prevents DNA replication, and corresponds directly with cell survival (14, 15).Several enzymes have been shown to catalyze the reduction of MC to reactive intermediates using either a one-electron or a two-electron mechanism. NADPH:cytochrome P-450 oxidoreductase (EC 1.6.2.4) (16, 17), NADH:cytochrome b 5 oxidoreductase (EC 1.6.2.2; FpD) (18, 19), xanthine:oxygen oxidoreductase (EC 1.1.3.22; xanthine oxidase) (16,20), and, more recently, nitric-oxide synthase (EC 1.14.13.39) (21,22) are among the enzymes using a one-electron reduction mechan...

show abstract

Randomized clinical trial of mitomycin c as an adjunct to radiotherapy in head and neck cancer

Cited by 186 publications

References 19 publications

Acridine Orange Excited by Low-Dose Radiation Has a Strong Cytocidal Effect on Mouse Osteosarcoma

Acridine Orange Excited by Low-Dose Radiation Has a Strong Cytocidal Effect on Mouse Osteosarcoma

SR 4233 (Tirapazamine): a new anticancer drug exploiting hypoxia in solid tumours

Nuclear Overexpression of NADH:Cytochromeb 5 Reductase Activity Increases the Cytotoxicity of Mitomycin C (MC) and the Total Number of MC-DNA Adducts in Chinese Hamster Ovary Cells

Contact Info

Product

Resources

About