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PubMed1996

Postlabeling detection of DNA adducts of antitumor alkylating agents.

The sensitivity for DNA adduct formation by antitumor alkylating agents (mechlorethamine, cisplatin and adozelesin) of the postlabeling technique and thin-layer chromatography was studied. Three DNAs were used: a double-stranded 20-bp oligonucleotide of defined sequence, calf thymus DNA and murine leukemia L1210 cellular DNA. With high concentrations of mechlorethamine, there was a marked decrease in normal dGp, a lesser decrease in dAp and dCp and no change in dTp. Using 2D mapping PEI-cellulose thin-layer chromatography analyses, it was found that six mechlorethamine: DNA adducts were produced after a short exposure to mechlorethamine. After an extended time at relatively high drug concentrations there was an alteration in the mechlorethamine: DNA adduct pattern that may reflect the conversion of monoadducts to crosslinked adducts. Similar observations were made with cisplatin and adozelesin. When murine leukemia L1210 cells were treated with 50 microM mechlorethamine or 50 microM cisplatin for 1 h, six or more mechlorethamine: DNA adducts and five cisplatin: DNA adducts were detected. After allowing 6 h. for repair of potentially lethal damage, several adducts were no longer detectable and others appeared with diminished intensity. Nuclease P(1) dephosphorylates normal nucleotides at relatively low enzyme concentrations with variation depending upon the nucleotide. In general, considerably lower concentrations of nuclease P1 were required to dephosphorylate the normal nucleotides than to dephosphorylate the antitumor alkylating agent: nucleotide adducts, thus allowing increased sensitivity of the postlabeling assay. The sensitivity of detection of antitumor alkylating agent: DNA adducts in DNA from treated L1210 cells approached one adduct per 10(7)-10(8) nucleotides. These results suggest that the postlabeling technique may be sufficiently sensitive and specific for the study of the clinically effective levels of antitumor alkylating agents.

Animals↗
PubMed1987

Effect of alkylating agents on the clearance of Staphylococcus aureus from murine lungs.

Alkylating agents have several effects on cellular host defense responses which could increase either the frequency or the severity of pulmonary infections. In addition, some of these agents directly injure lung parenchyma and could have effects on intrapulmonary killing processes independent of any effect on phagocyte number and function. We have used a murine model for staphylococcal clearance to evaluate the effect of cyclophosphamide and mechlorethamine on intrinsic lung defenses. Single doses of mechlorethamine (40 micrograms IV) or of cyclophosphamide (150 mg/kg IP) reduce peripheral blood neutrophil counts and spleen weights on day 3 after injection; with the exception of neutrophil counts in mechlorethamine-treated mice, these parameters returned to normal by days 10-12. Both drugs reduced the number of alveolar macrophages recoverable by bronchoalveolar lavage on days 10-12 but not day 3. Mechlorethamine delayed the clearance of Staphylococcus aureus 502A from the lung on both days 3 and 12, but cyclophosphamide did not alter clearance on either day 3 or 10. The defect in clearance in mechlorenthamine-treated mice resolved by 3 wk after drug administration. These results demonstrate that alkylating agents do not have uniform effects on antibacterial processes in the murine lung. Since the mechlorethamine effect on staphylococcal elimination appears independent of its effect on macrophage numbers, these results suggest that staphylococcal clearance also depends on nonphagocytic host defense factors.

Alkylating Agents↗
PubMed1989

Dose intensity of MOPP chemotherapy and survival in Hodgkin's disease.

The association between dose intensity of chemotherapy with the rate of complete remission (CR), the duration of disease-free survival (DFS), and overall survival (OS) was separately analyzed for 67 patients initially treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), and for 75 patients in relapse following radiotherapy who had received MOPP as a salvage regimen. In both groups of patients, the fraction of the total dose of mechlorethamine delivered in all cycles divided by the planned dose for six cycles was strongly associated with OS (P = .002 for patients receiving initial MOPP and P = .02 for the salvage group, respectively). B symptoms were independent of drug-derived variables associated with OS (corresponding P values .03 for initial MOPP and .004 for the salvage group). The predictive value of mechlorethamine dosage with regard to OS was retained in an analysis restricted to the patients receiving greater than or equal to six cycles of chemotherapy. In the initial chemotherapy group, mechlorethamine dosage was associated with attainment of CR but none of the variables tested was predictive of DFS. In the salvage chemotherapy group, mechlorethamine dosage was associated with attainment of CR and duration of DFS as well. The results emphasize that, besides tumor characteristics, optimal dosage of chemotherapy is of great importance for survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Therapeutic options in patients with lymphoma and severe liver dysfunction.

OBJECTIVES: To determine the long-term outcome of patients presenting with synchronous lymphoma and severe liver dysfunction and to describe the outcome of patients treated with initial mechlorethamine-based therapy used as a bridge to more conventional chemotherapy. PATIENTS AND METHODS: We reviewed the clinical course of all patients diagnosed as having lymphoma who presented with severe liver dysfunction and received intravenous mechlorethamine between September 1988 and February 2003 at the Mayo Clinic in Rochester, Minn. RESULTS: Forty-one patients were identified, 33 (80%) of whom had newly diagnosed, previously untreated lymphoma. Thirty-seven (90%) had non-Hodgkin lymphoma, and 4 (10%) had Hodgkin disease. Thirty-four patients (83%) had stage IV disease, and 31 (84%) of 37 had an intermediate-high International Prognostic Index. The median total bilirubin level before therapy was 10.7 mg/dL (range, 2.5-30.2 mg/dL), and the median alkaline phosphatase level was 982 U/L (range, 233-3415 U/L). In addition to mechlorethamine, 34 patients (83%) received concomitant corticosteroids, and 12 (29%) received concomitant rituximab. Twenty-two patients (54%) had sufficient improvement in liver function to receive subsequent standard chemotherapy. Nine patients (22%) are alive and disease-free at a median of 31 months (range, 4 to > or = 87 months) after mechlorethamine treatment. Factors associated with improved overall survival included improvement in bilirubin levels (P < .001) and receiving subsequent standard chemotherapy (P = .001). CONCLUSION: Mechlorethamine, high-dose corticosteroids, and rituximab are useful therapeutic interventions for this unique group of patients with lymphoma and severe liver dysfunction. Substantial clinical improvement and long-term survival are possible.

Adrenal Cortex Hormones↗