Clinical trial of maintenance therapy with cyclophosphamide vs misonidazole and cyclophosphamide in patients with non oat cell unoperable lung carcinoma already treated with misonidazole and radiation

Rimondi, C; Busutti, L.; Breccia, A.

doi:10.1016/0360-3016(82)90741-6

International Journal of Radiation Oncology*Biology*Physics

1982

DOI: 10.1016/0360-3016(82)90741-6

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Clinical trial of maintenance therapy with cyclophosphamide vs misonidazole and cyclophosphamide in patients with non oat cell unoperable lung carcinoma already treated with misonidazole and radiation

C Rimondi¹,

L. Busutti²,

A. Breccia³

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1983

1984

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Cited by 2 publications

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“…As a result, Phase I clinical studies of MISO in combination with CYT and L-PAM are currently in progress (Rimondi et al, 1982;Klein et al, 1982;Coleman et al, 1983).…”

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confidence: 99%

Enhancement of melphalan-induced tumour cell killing by misonidazole: An interaction of competing mechanisms

Horsman¹,

Evans²,

Brown³

1984

Br J Cancer

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Summary In the present studies we have used the RIF-I tumour in C3H mice to try to identify the mechanism(s) responsible for the enhancement of melphalan (L-PAM) induced tumour cell killing by the 2-nitroimidazole misonidazole (MISO). Most of this work was done with a single large dose of MISO (750mgkg-1) given 30min before injection of L-PAM. We found no effect of MISO on the repair of L-PAM-induced potentially lethal damage (PLD) as measured using an in vitro clonogenic survival assay. However, we identified three interrelated and competing processes which affect tumour cell killing by L-PAM subsequent to MISO injection. First, MISO reduces the clearance rate of L-PAM from the blood, an effect which enhances the cell killing by L-PAM. Second, MISO reduces the body temperature which produces a significant reduction in L-PAM cytotoxicity. Third, there is an enhancement of L-PAM cell killing by MISO over and above these two competing processes which is probably a result of the same mechanism by which cells in vitro are sensitized to L-PAM by pre-exposure to MISO under hypoxic conditions. Considerable interest has been shown in combining conventional anti-tumour agents and nitroaromatic radiation sensitizers, especially the 2-nitroimidazoles. Of the chemotherapeutic agents tested in mouse tumour models, the results to date indicate that misonidazole (MISO) shows its greatest interaction with the bifunctional alkylating agents cyclophosphamide (CYT), melphalan (L-PAM), and the nitrosoureas, especially CCNU (1-[2-chloroethyl]-3-cyclohexyl-l-nitrosourea) (McNally, 1982;Siemann, 1982).In general, tumour toxicity is enhanced to a greater degree than is the response of normal tissues. As a result, Phase I clinical studies of MISO in combination with CYT and L-PAM are currently in progress (Rimondi et al., 1982;Klein et al., 1982;Coleman et al., 1983).At the present time, the mechanisms for the chemosensitization of alkylating agents by MISO remain unclear. Several processes have been implicated. These include selective killing of hypoxic cells by MISO, changes in the pharmacokinetics and/or metabolism of drugs by MISO, interference with the repair of potentially lethal damage (PLD) induced by the chemotherapeutic agent, and a manifestation of the in vitro chemosensitization obtained by preexposure of cells to MISO under hypoxic conditions (Brown, 1982;Siemann, 1982).In the present study we have used the RIF-I tumour model to investigate the mechanism by which MISO sensitizes these tumour cells to L-PAM. Materials and methods Tumour systemThe RIF-l tumour used in the present study is a non-immunogenic sarcoma in its syngeneic host (the C3H/Km mouse) and has been developed for in vivo-in vitro assay (Twentyman et al., 1980). It is routinely maintained by passage in vitro. Solid tumours were produced in 3-4 month old female C3H/Km mice by innoculating 2 x 105 cells in a volume of 0.05 ml into the base of the gastrocnemius muscle in the right rear leg. Tumour growth was followed by measuring two leg diameters at right angle...

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“…As a result, Phase I clinical studies of MISO in combination with CYT and L-PAM are currently in progress (Rimondi et al, 1982;Klein et al, 1982;Coleman et al, 1983).…”

mentioning

confidence: 99%

Enhancement of melphalan-induced tumour cell killing by misonidazole: An interaction of competing mechanisms

Horsman¹,

Evans²,

Brown³

1984

Br J Cancer

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“…MISO enhancement ratios are usually between 1.2-3.1 for tumour response and between 1.2-1.9 for normal tissue toxicity, such as myelosuppression or low white blood cell count (Fowler, 1982). Phase I clinical studies of MISO in combination with DNA cross-linking agents are currently in progress (Rimondi et al, 1982;Klein et al, 1982).…”

mentioning

confidence: 99%

Enhancement of the DNA cross-linking activity of melphalan by misonidazole in vivo

Murray¹,

Meyn²

1983

Br J Cancer

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Clinical trial of maintenance therapy with cyclophosphamide vs misonidazole and cyclophosphamide in patients with non oat cell unoperable lung carcinoma already treated with misonidazole and radiation

Cited by 2 publications

References 0 publications

Enhancement of melphalan-induced tumour cell killing by misonidazole: An interaction of competing mechanisms

Enhancement of melphalan-induced tumour cell killing by misonidazole: An interaction of competing mechanisms

Enhancement of the DNA cross-linking activity of melphalan by misonidazole in vivo

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