Emergence of nitrosourea resistant sublines of Lewis lung tumour following MeCCNU treatment in vivo

Stephens, T C; Adams, K; Peacock, John

doi:10.1038/bjc.1986.41

Cited by 8 publications

(4 citation statements)

References 9 publications

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“…The 3Lewis-lung carcinoma that arose spontaneously in 1951 in a C57B1/6 mouse (41) is highly malignant and metastasizes regularly to the lungs (41)(42)(43), probably due to its lack of immunogenicity in syngeneic recipients (44,45). Furthermore, this tumor is, as are human solid cancers, characterized by a primary resistance to a majority of chemotherapeutics (46)(47)(48)(49)(50).…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activity of Ilmofosine (BM 41.440) in the 3Lewis-Lung Carcinoma Model

Herrmann¹,

Opitz²,

Munder³

1992

Platelet-Activating Factor and Structurally Related Alkyl Ehter Lipids

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Ilmofosine (1 -hexadecylthio-2-methoxymethyl-1,3. propanediol-phosphocholine, BM 41.440) is a thioether phospholipid with cytostatic/cytotoxic properties. The antineoplastic activity of this compound was investigated in vivo in the 3Lewis-lung carcinoma system. 3Lewis lung tumor-bearing C57B1/6 mice were treated with 0.625 to 40 mg I1mofosine/kg per day p.o. either from days 1 to 9 or from days 11 to 28 after intrafoot-pad tumor cell inoculation. Ilmofosine caused a significant doserelated response on tumor growth and metastases, expressed in terms of tumor diameter, tumor weight, survival time and number of metastasesfree animals as compared to sham-treated and positive (cyclophosphamide) controls. The results suggest that direct cytostatic/cytotoxic effects, rather than immune-modulatory mechanisms, preferentially contribute to the antitumor activity of Ilmofosine in vivo. Lipids 26, 1431-1436 (1991).

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Section: Discussionmentioning

confidence: 99%

Antitumor Activity of Ilmofosine (BM 41.440) in the 3Lewis-Lung Carcinoma Model

Herrmann¹,

Opitz²,

Munder³

1992

Platelet-Activating Factor and Structurally Related Alkyl Ehter Lipids

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“…We established that this effect was due to a direct effect of CZT on the tumour cells, rather than on the host, as treatment of the rats prior to the injection of RMS 9-4/0 did not give the same results (Poupon et al, 1984). We suspected a CZT-resistant subpopulation of the tumour to be highly metastatic, associating genetic instability and metastatic ability (Cifone & Fidler, 1981) and the postulated relationship between genetic instability and progression to a more drug-resistant phenotype by means of the generation and selection of variants (Goldie & Coldman, 1984;Stephens et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

“…The probability that a tumour will generate resistant variants could be related to genetic instability (Goldie & Coldman, 1984;Stephens et al, 1986). According to Cifone and Fidler (1981), genetic instability is also an important characteristic of metastatic cell lines.…”

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confidence: 99%

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In vivo emergence of a highly metastatic tumour cell line from a rat rhabdomyosarcoma after treatment with an alkylating agent

Antoine

Pauwels²,

Verrelle³

et al. 1988

Br J Cancer

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Summary Rats bearing a transplanted nickel-induced rhabdomyosarcoma (RMS 9-4/0), treated with chlorozotocin (CZT), an alkylating agent, showed an amplified metastatic invasion of the lung (median of 165 lung tumour nodules, compared to 3 for untreated controls). A higher level of metastatic invasion (200 nodules) was reached spontaneously after the grafting of the S4T line, which was obtained by successive in vivo passages of RMS 9-4/0 cells in CZT treated rats. S4T tumour cells also invaded the liver and a considerable proportion of the lymph nodes. The NT4T line, obtained by successive in vivo passages in untreated rats, showed a lesser degree of enhancement of metastatic capacity (57 nodules). Both derived lines proved to be more aggressive than the parental, proliferated more rapidly, and were resistant to CZT toxicity. Only the non-treated lineage became more resistant to NK lysis. The S4T line lost its myogenic differentiation and was best described as a fibrohistiosarcoma, whereas NT4T did not. Chromosome analysis demonstrated a reduced range of chromosome number per cell in both lines. We conclude that both S4T and NT4T tumours became more metastatic than RMS 9-4/0 as the result of tumour progression through in vivo passages, and that in addition S4T acquired a spontaneously higher metastatic potential, similar to that which occurred in rats grafted with RMS 9-4/0 or NT4T tumours and treated by CZT. This suggests an inheritable mutation in the S4T line.A major problem of cancer therapy is the emergence of tumour subpopulations resistant to the treatment. The probability that a tumour will generate resistant variants could be related to genetic instability (Goldie & Coldman, 1984;Stephens et al., 1986 Davies, 1982). Repair mechanisms may allow mutated cells to survive, and increase both tumour drug resistance and phenotypic heterogeneity.We have described the enhancing effect of a nitrosourea, chlorozotocin 2-(3-(2-chloroethyl)-3-nitrosoureido)-D-glucopyranose (CZT), on the metastatic ability of RMS 9-4/0, a rat rhabdomyosarcoma (Poupon et al., 1984). We hypothesized that this action was due to the emergence of a subpopulation of the RMS 9-4/0 tumour, that was both resistant to CZT and highly metastatic. We failed to obtain a selection for CZT resistance in the primary tumour because the treated rats were rapidly killed by the growth of lung metastases. To overcome this, the treated primary tumour cells were injected into new recipients that were also treated and this cycle was repeated until a fully resistant population was obtained. The metastatic ability of these cells was then studied. A group of the tumour-bearing rats were not drug-treated and gave rise to the NT(x)T tumour lineage, where (x) designates the number of cycles performed. When rats were moribund the tumour was excised, finely minced with a scalpel, and then allowed to grow in the complete medium described above. At confluence, cells were injected s.c. into new animals. Part of the cells were frozen for further analyses. Materials and me...

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Drug resistance and DNA repair

Fox

Roberts

1987

Cancer Metast Rev

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DNA repair confers resistance to anticancer drugs which kill cells by reacting with DNA. A review of our current information on the topic will be presented here. Our understanding of the molecular biology of repair of 0(6)-alkylguanine adducts in DNA has advanced as a result of the molecular cloning of the E. coli ada gene but the precise role of this lesion in the cytotoxic effects of alkylating agents in mammalian cells is not completely understood. Less progress has been made in understanding the enzymology and molecular biology of DNA cross-link repair even though such lesions are important for the cytotoxic effects of the widely used bifunctional alkylating agents and platinum compounds. It is evident that drug sensitive or resistant phenotypes are as highly complex as are the effects of DNA damage on cell metabolism and various aspects of these effects are discussed. Few clear correlations have been made between quantitative differences in DNA repair capacity and cellular sensitivity but assays which were developed to measure fidelity and intragenomic heterogeneity in DNA repair are beginning to be applied. Such studies may reveal subtle differences between sensitive and resistant cell lines. The molecular cloning of human DNA repair genes by transfection into drug sensitive rodent cells has been attempted. Some success has been achieved in this area but the functions of the cloned genes have yet to be identified.

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Emergence of nitrosourea resistant sublines of Lewis lung tumour following MeCCNU treatment in vivo

Cited by 8 publications

References 9 publications

Antitumor Activity of Ilmofosine (BM 41.440) in the 3Lewis-Lung Carcinoma Model

Antitumor Activity of Ilmofosine (BM 41.440) in the 3Lewis-Lung Carcinoma Model

In vivo emergence of a highly metastatic tumour cell line from a rat rhabdomyosarcoma after treatment with an alkylating agent

Drug resistance and DNA repair

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