The nitrosoureas and pulmonary toxicity

Weiss, Raymond B.; Poster, Don S.; Penta, John S.

doi:10.1016/s0305-7372(81)80031-x

Cited by 86 publications

(23 citation statements)

References 39 publications

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“…Follow-up studies in another 10 patients showed a significant sub-clinical deterioration in lung function following chemotherapy (Table V). The clinical, radiological and histological features of 'early onset' lung fibrosis have previously been described with BCNU and other nitrosoureas (Bailey et al, 1978;Durant et al, 1979;Aronin et al, 1980;Sekler et al, 1980;Weiss et al, 1981); correlation is seen when cumulative dosage of BCNU > 1000mgm2 (Weiss et al, 1981). However, the two cases of interstitial pneumonitis in our study received a cumulative dosage of < 400 mg m-2 of fotemustine suggesting that the synergy between DTIC and fotemustine (as used in the schedule here) may be responsible for the acute pulmonary event, possibly related to greater cytotoxicity in normal lung cells following depletion of the endogenous ATase.…”

Section: Discussionmentioning

confidence: 90%

Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma

Lee

Margison²,

Woodcock³

et al. 1993

Br J Cancer

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Summary There is increasing experimental evidence to suggest that expression of 06-alkylguanine-DNAalkyltransferase (ATase) is a major factor in resistance to dacarbazine (DTIC). We recently demonstrated a progressive ATase depletion in human peripheral lymphocytes with nadir levels occurring at 4-6 h after DTIC administration (Lee et al., 1991). Therefore in an attempt to improve the clinical response rate of DTIC, fotemustine was administered 4 h after DTIC administration; since in the case of fotemustine, ATase removes the chloroethyl lesions from the 06-position of guanine, thereby preventing the formation of the cytotoxic cross-links. Sixty patients with widely metastatic melanoma received DTIC at 400, 500 or 800 mg m-2 followed by fotemustine (100 mg m') at 4 h after DTIC administration. Treatment was repeated every 28 days with a total of 169 cycles of chemotherapy administered; 75, 57 and 37 treatment cycles with 400, 500 and 800mg m2 DTIC groups respectively. Eighteen of the 60 patients responded (with three complete response); response rates were linearly related to dose, being 24%, 30% and 40% in patients receiving 400, 500 and 800 mg m-2 of DTIC respectively and the overall response rate was 30%. Median survival was 3.6 months (range, 1-15 months) with no statistically significant difference between the different DTIC treatment groups (P = 0.67). Nine patients are alive at 5 to 26 months (median 10 months); three patients with no tumour and five patients with stable disease. A statistically significant relationship was seen between the development of severe haematological toxicity (WHO > 3) with increasing dosage of DTIC and significant subclinical pulmonary damage was seen in 11 patients where the lung function was monitored during the course of treatment. In conclusion, it appears that with this small group of patients, escalation of DTIC dosage might not significantly affect response rates but does increase haematological toxicity. The present study provides a framework for other studies in an attempt to modulate ATase-mediated drug resistance in tumour tissues but the associated toxicity will need careful monitoring.

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Section: Discussionmentioning

confidence: 90%

Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma

Lee

Margison²,

Woodcock³

et al. 1993

Br J Cancer

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“…The dose required to block DNA synthesis in cells treated shortly after receiving fresh RPMI-serum, when they were still in the lag phase, was 1O-fold smaller than that needed to produce an equivalent effect if the cells were treated 17 h later, when they were in log phase. The impact of BCNU was therefore characteristically time dependent, as in patients receiving chemotherapy (12,15,38,39).…”

Section: Discussionmentioning

confidence: 99%

“…We were surprised to observe that later, in bloods obtained 10, 14, and 16 wk after the last (sixth) weekly course of BCNU, the levels of erythrocyte GSH were much higher than they had been in the basal pre-chemotherapy samples (4). In subsequent years, the inhibition ofGSSG-R by BCNU became widely used to probe the impact ofaltered GSH oxidoreduction in many biological contexts, new pleiotropic drug effects were uncovered (5-1 1), GSSG-R deficiency was incriminated etiologically in delayed pulmonary toxicity (12)(13)(14)(15), the "rebound" increase ofGSH after exposure to the drug was confirmed in several systems ( 13,14,16), and impressive progress was made in clarifying the role of 06-alkylated guanine adduct formation and repair in the pharmacology of nitrosoureas (17)(18)(19)(20)(21)(22)(23)(24)(25). Nevertheless, several aspects ofthe biological response to these agents remain poorly understood, including the potential relationship between antitumor effects and thiol alterations.…”

Section: Introductionmentioning

confidence: 99%

Glutathione, cell proliferation, and 1,3-bis-(2-chloroethyl)-1-nitrosourea in K562 leukemia.

Frischer¹,

Kennedy²,

Chigurupati³

et al. 1993

J. Clin. Invest.

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We have pursued our findings ofglutathione reductase (GSSG-R) deficiency and disturbed glutathione in cancer patients treated with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), by investigating how thiol metabolism, cell proliferation, and the nitrosourea interact in human K562 leukemia. Fasting cells arrested in G greatly increased their reduced glutathione (GSH) in response to growth factors. The rise in thiol began after several hours, peaked before DNA synthesis, and resulted from increased production. BCNU inactivated GSSG-R rapidly, and later retarded, doubled, and greatly prolonged GSH formation before stopping DNA synthesis. Pretreatment unlike post treatment with buthionine-S-R-sulfoximine (BSO) diminished BCNU's ability to block GSSG-R. Enzyme inhibition decreased with falling cellular GSH. In the leukemia system as in vivo, sequential BCNU-induced thiol alterations heralded delayed antiproliferative effects. Drug timing markedly affected both thiol and DNA syntheses. By destroying GSSG-R and delaying the upregulation of thiol synthesis while escalating GSH utilization and requirements, the nitrosourea created a striking and previously unrecognized window of vulnerability for GSH-dependent processes. During this period, altered GSH metabolism could contribute indirectly to BCNU's pleiotropic effects by interfering with DNA alkylation repair, glucose decarboxylation, deoxyribose formation, and possibly by influencing other aspects of proliferation. Acquired GSSG-R deficiency was also an early and sensitive marker for prodrug breakdown and activation. (J. Clin. Invest. 1993. 92:2761-2767

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“…Proposed mechanisms of BCNU-induced pulmonary toxicity include DNA damage, glutathione depletion, or adverse inflammation and an immune response in the lung (6, 22). The pathological changes of BCNU-induced pulmonary toxicity include alveolar edema and protein accumulation, diffuse hyperplasia, and hypertrophy of alveolar epithelial cells, metaplasia of alveolar epithelium, fibroblastic proliferation in the alveolar septae, and alveolar septal fibrosis (23,35).As an alkylating agent, BCNU causes DNA damage by modifying bases, cross-linking, and inducing DNA strand breaks (37). BCNU alkylates DNA predominantly (Ͼ90%) at N 7 positions of guanine and to a less extent, at the O 6 position of guanine (32).…”

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confidence: 99%

Escherichia coliFPG and human OGG1 reduce DNA damage and cytotoxicity by BCNU in human lung cells

Kobune³

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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To increase the resistance of lung cells to BCNU, we employed gene transfer of Escherichia coli formamidopyrimidine-DNA glycosylase (FPG) and human 8-oxoguanine-DNA glycosylase (hOGG1) to A549 cells, a lung epithelial cell line, using a bicistronic retroviral vector, pSF91-RE, that encoded both FPG/hOGG1 and an enhanced green fluorescent protein. The transduced epithelial cells were sorted by flow cytometry, and expression of FPG/hOGG1 protein was determined by the level of FPG/hOGG1 RNA and enzyme activity. The single-cell gel electrophoresis (comet assay) measured DNA damage induced by BCNU. FPG/hOGG1-expressing A549 cells incubated with 40-500 g/ml BCNU exhibited significantly less DNA damage than vector-transduced cells. In addition, FPG-and/or hOGG1-expressing cells incubated with 10-40 g/ml BCNU showed at least a 25% increase in cell survival. Gene transfer of FPG/hOGG1 reduced BCNUinduced DNA damage and cytotoxicity of cultured lung cells and may suggest a new mechanism to reduce BCNU pulmonary toxicity. deoxyribonucleic acid repair; pulmonary toxicity; N 7 -alkylated guanine; formamidopyrimidine-DNA glycosylase; human 8-oxoguanine-DNA glycosylase; 1,3-N,NЈ-bis(2-chloroethyl)-N-nitrosourea PULMONARY COMPLICATIONS of cancer chemotherapy are common (36). Although many chemotherapeutic drugs damage DNA in neoplastic cells, these drugs can also damage DNA in normal lung cells, resulting in both early-onset and delayed-onset pulmonary disorders (36). Because pulmonary toxicity remains one of the major adverse reactions limiting the use of more aggressive anticancer regimens (36), correcting or preventing the genotoxic and/or cytotoxic effects to lung cells would likely improve the therapeutic efficacy of these regimens.1,3-N,NЈ-bis(2-chloroethyl)-N-nitrosourea (BCNU) is a chemotherapeutic drug commonly used for human intracranial tumors, Hodgkin's disease, non-Hodgkin's lymphomas, melanoma, and gastrointestinal cancer (34,36). In addition to bone marrow suppression and gastrointestinal toxicity, pulmonary toxicity by BCNU is a major fatal complication and occurs in as high as 20-30% of the patients treated by BCNU (34,35). Proposed mechanisms of BCNU-induced pulmonary toxicity include DNA damage, glutathione depletion, or adverse inflammation and an immune response in the lung (6, 22). The pathological changes of BCNU-induced pulmonary toxicity include alveolar edema and protein accumulation, diffuse hyperplasia, and hypertrophy of alveolar epithelial cells, metaplasia of alveolar epithelium, fibroblastic proliferation in the alveolar septae, and alveolar septal fibrosis (23,35).As an alkylating agent, BCNU causes DNA damage by modifying bases, cross-linking, and inducing DNA strand breaks (37). BCNU alkylates DNA predominantly (Ͼ90%) at N 7 positions of guanine and to a less extent, at the O 6 position of guanine (32). O 6 adducts result in miscoding and subsequently cause interstrand cross-linking as well, so they account for both mutagenic and cytotoxic activities of BCNU (37). The O 6 guanine adducts gener...

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The nitrosoureas and pulmonary toxicity

Cited by 86 publications

References 39 publications

Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma

Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma

Glutathione, cell proliferation, and 1,3-bis-(2-chloroethyl)-1-nitrosourea in K562 leukemia.

Escherichia coliFPG and human OGG1 reduce DNA damage and cytotoxicity by BCNU in human lung cells

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