Drug resistance and DNA repair

Fox, Margaret; Roberts, J. J.

doi:10.1007/bf00144267

Cited by 43 publications

(12 citation statements)

References 91 publications

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“…The overall relationship between DNA repair and cellular sensitivity to alkylating agents has not been established, nor are the processes involved completely understood (Fox & Roberts 1987). The enzyme that has been studied most extensively is 06-alkylguanine-DNA-alkyltransferase, which repairs damage caused by nitrosoureas, and it appears that enhanced activity of this enzyme influences the ability to recover from cytotoxic damage.…”

Section: Methylxanthinesmentioning

confidence: 99%

Clinical Pharmacokinetics of Cyclophosphamide

Moore

1991

Clinical Pharmacokinetics

255

131

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Cyclophosphamide has been in clinical use for the treatment of malignant disease for over 30 years. It remains one of the most useful anticancer agents, and is also widely used for its immunosuppressive properties. Cyclophosphamide is inactive until it undergoes hepatic transformation to form 4-hydroxycyclophosphamide, which then breaks down to form the ultimate alkylating agent, phosphoramide mustard. Sensitive and specific methods are now available for the measurement of cyclophosphamide, its metabolites and its stereoisomers in plasma and urine. The pharmacokinetics of cyclophosphamide have been understood for many years; those of the cytotoxic metabolites have been described more recently. The pharmacokinetics are not significantly altered in the presence of hepatic or renal insufficiency. As activity resides exclusively in the metabolites, whose pharmacokinetics are not predicted by those of the parent compound, correlations between cyclophosphamide pharmacokinetics and pharmacodynamics have not been demonstrated. Cyclophosphamide is used in doses that range from 1.5 to 60 mg/kg/day. A steep dose-response curve exists, and reductions in dose can lead to unfavourable outcomes. Myelosuppression is the dose-limiting toxicity, although in the setting of bone marrow transplantation, escalation beyond that dosage range is limited by cardiac toxicity. Longer term complications of cyclophosphamide therapy include infertility and an increased incidence of second malignancies. Cellular sensitivity to cyclophosphamide is a function of cellular thiol concentration, metabolism by aldehyde dehydrogenases to form inactive metabolites, and the ability of DNA to repair alkylated nucleotides. Whether alteration of these cellular functions will lead to further improvements in clinical outcomes is an area of active investigation.

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Section: Methylxanthinesmentioning

confidence: 99%

Clinical Pharmacokinetics of Cyclophosphamide

Moore

1991

Clinical Pharmacokinetics

255

131

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“…Accordingly, at present at least three different types of cellular mechanisms for drug resistance have been identified: (a) those by which cells inactivate or eliminate drugs; (b) those in which there is an increase in the activity of the mechanisms involved in repairing the damage caused by the drugs; and (c) antiapoptotic mechanisms which, independent of the existence or not of cell damage, prevent cells from undergoing apoptosis and provide an opportunity for the repair systems to replace damaged cellular components once chemotherapy is either reduced or stopped [5,6,9,13,27,29,33].…”

Section: Introductionmentioning

confidence: 99%

Functional expression of MDR-1 in acute myeloid leukemia: correlation with the clinical-biological, immunophenotypical, and prognostic disease characteristics

Martínez

Miguel

Valverde

et al. 1997

Annals of Hematology

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Up till now, clinical data on the possible prognostic influence of multidrug resistance (MDR) in hematological malignancies have been inconsistent, probably due to technical pitfalls. Moreover, in most studies qualitative information on the presence/absence of MDR-1 expression has been used instead of quantitative results. In addition, results usually refer to the total BM population and not specifically to blast cells. In the present study we analyzed the expression of MDR-1 in a series of 50 newly diagnosed de novo AML using a double-staining technique: (a) monoclonal antibodies for the specific identification of blast cells and (b) the rhodamine-123 efflux assay, which allows a quantitative and calibrated measurement of MDR-1 function. Expression of MDR-1 was correlated with clinical, biological, and immunophenotypical disease characteristics. All patients were uniformly treated according to the AML 87/91 protocols of the Spanish Pethema Cooperative Group; the median age was 51 +/- 19 years and the FAB distribution was as follows: 2 M0, 9 M1, 9 M2, 12 M3, 11 M4, 5 M5, and 2 M6 cases. Upon grouping the 50 AML patients analyzed according to the level of rh123 elimination, it was observed that those cases with > or = 30% decrease in rh123 fluorescence displayed higher WBC counts (9 +/- 12 vs 37 +/- 73 x 10(9)/l, p = 0.02) and platelet numbers (94 +/- 11 vs 35 +/- 25 x 10(9)/l, p = 0.02), together with a higher incidence of extramedullary involvement (35% vs 24%, p = 0.02). Half of the patients (47%) displaying a low rh123 elimination (< 30%) showed M3 morphology, while among the 33 patients with a higher rate of rh123 elimination (> or = 30%), only four (12%) corresponded to the M3 morphological subtype (p = 0.0006). From the immunophenotypic point of view, a low rate of rh123 elimination was associated with a lower expression of HLADR antigen (p = 0.003) and a higher expression of CD117 (p = 0.01). Regarding the possible prognostic influence of MDR1 expression, we found that a high rate of rh123 elimination (> 30%) was associated with a tendency towards poor disease outcome, illustrated by both a lower complete remission rate with the first cycle of chemotherapy (36% vs 56%) and a lower median disease-free survival (22 months vs median DFS not reached), although differences did not reach statistical significance (p = 0.1 in both comparisons). This data shows that although MDR-1 can be a relevant parameter in the evaluation of AML patients, larger series of patients using appropriate techniques for specifically analyzing the MDR of blast cells will be necessary in order to establish the final clinical value of this parameter.

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“…For example mis-match repair and base excision repair can deal with sublethal damage induced by ionising radiation such as UV and X-rays, and also DNA damage caused by alkylating agents and cisplatin [76,77]. Eukaryotic cells can also induce a heat shock response following mild hyperthermia.…”

Section: Damage Limitation and Repairmentioning

confidence: 99%