Uracil mustard and 5-fluorouracil combination chemotherapy: a historic record.

BACKGROUND: Uracil mustard and 5-fluorouracil (UM-FU) combination chemotherapy was used as one of the earliest combination chemotherapies in ovarian carcinoma from 1964 to 1971 at Yale New Haven Medical Center. METHODS: UM-FU was offered to patients with stage III and IV, histologically verified, ovarian carcinoma. Uracyl mustard was administered orally--1 mg/ kg, daily. 5-Fluorouracyl was administered every four weeks at 5 mg/kg for five days by intravenous infusion. RESULTS: Of a total 185 patients with ovarian cancer, 76 received UM-FU. Thirty-five patients had measurable disease. Fifteen (42%) showed objective response lasting three to 95 months, with decrease in size of masses and disappearance of ascites or hydrothorax. Their survival from diagnosis to death was 41 months. Twenty patients showed no response; their mean survival was 18 months. Three of the 76 patients who received UM-FU developed acute nonlymphocytic leukemia. CONCLUSION: UM-FU was effective in controlling ascites and hydrothorax and diminished intraabdominal masses. The discovery of adriamycin and then platinum led to more effective therapy and the use of uracil mustard was superseded. It is no longer available. The experience reported is of historic interest.

[Study on the chemical constituents qf Spongilla Wagner].

OBJECTIVE: To study the chemical constituents in the fresh marine sponge Spongilla Wagner. METHODS: Compounds were separated and purified through various chromatographic methods and their structures were identified by spectroscopic data. RESULTS: Seven compounds were isolated and identified as 4-hydroxybenzoic acid (I), p-hydroxycinnamic acid (II), Pyrimidine-2, 4 (1H, 3H)-dione (III), Ferulic acid methyl ester (IV), Dodecyl ethers of glycerol (V), Tetracosane( VI). CONCLUSION: All compounds are isolated from this sponge for the first time.

Design, synthesis, and biological activity of hybrid compounds between uramustine and DNA minor groove binder distamycin A.

The design, synthesis, characterization, DNA binding properties, and cytotoxic activity of a novel series of hybrids, namely, a molecular combination of the natural antibiotic distamycin A and the antineoplastic agent uramustine, are reported, and the structure-activity relationships are discussed. This homologous series 29-34 consisted of the minor groove binder distamycin A joined to uramustine (uracil mustard) by suitable aliphatic carboxylic acid moieties containing a flexible polymethylene chain that is variable in length [(CH(2))(n)(), where n = 1-6). All the hybrid compounds in this series exhibit enhanced activity compared to both distamycin A and uramustine derivatives 22-27 used for conjugation, giving IC(50) values in the range 7.26-0.07 microM following a 1 h exposure of human leukemic K562 cells, with maximal activity shown when n = 6. The distance between the uramustine and distamycin frame is crucial for the cytotoxicity, with compounds having linker lengths of four to six being at least 20-fold more cytotoxic than linker lengths one to three. Taq polymerase stop experiments demonstrated selective covalent binding of uramustine-distamycin hybrids to A/T rich DNA sequences, which was again more efficient with compounds 32-34 with a longer linker length. Two consequences can be derived from our study: (a) the distamycin moiety directs binding to the minor groove of A/T rich DNA sequences and, consequently, is responsible for the alkylation regioselectivity found in footprinting studies; (b) the higher flexibility due to a longer linker between the distamycin and uracil moieties allows the formation of complexes with the mustard moiety situated more deeply in the minor groove and, hence, with better alkylating properties.

Uracil mustard revisited.

BACKGROUND: A patient with diffuse large cell lymphoma who had a complete response lasting 35 years following a 3-day course of uracil mustard stimulated a recall review of patients treated with this oral alkylating agent. METHODS: Records of patients treated with uracil mustard between 1958 and 1970 were reviewed. A current histologic review according to the International Formulation was performed when possible. Total doses of uracil mustard were similar to those of mechlorethamine, although there were variations in the dose schedule. RESULTS: Employing criteria used over 25 years ago to evaluate patients' responses, the overall regression rate for 94 non-Hodgkin lymphoma patients was 69.2% (complete response [CR] 23.4%). Of 62 patients with Hodgkin disease, 69.4% responded (CR 9.7%). For 39 patients with chronic lymphatic leukemia, the combined complete and partial response rate was 74% (CR 7.7%). Thrombocytopenia was the primary toxicity. CONCLUSIONS: Uracil mustard is an unmarketed, inexpensive oral alkylating agent that has been effective in the treatment of patients with lymphoma, chronic lymphatic leukemia, and thrombocythemia. Perhaps it should be reevaluated.

Progression of essential thrombocythemia to blastic crisis via idiopathic myelofibrosis.

We report a 61-year-old man with essential thrombocythemia (ET) whose clinical course was followed for 12 years. The ET evolved into true idiopathic myelofibrosis (IM) 6 years after the initial diagnosis and progressed to myeloid blastic transformation 6 years later. The cytogenetic analysis showed a normal karyotype during the ET phase but subsequent analysis revealed an abnormal karyotype during the IM phase which evolved clonally at blastic crisis with constant involvement of chromosome 13q and chromosome 7. The close monitoring of essential events, using clinical, morphologic, immunologic and cytogenetic parameters, allowed us to carefully identify the transition from one chronic myeloproliferative disease (MPD) to another. This is only the second case reported showing a clinical evolution of this nature. The clinical and biological aspects of the disease are briefly discussed.

An application of 3D-QSAR to the analysis of the sequence specificity of DNA alkylation by uracil mustard.

The sequence specificity of DNA alkylation by uracil mustard was examined using a novel three-dimensional QSAR method known as HASL, or the hypothetical active site lattice. The structures of a variety of 4-mer sequences obtained from pBR322 and SV40 were related to their degree of guanine-N7 alkylation by uracil mustard. The resulting correlations were found to point to a significant contribution from bases on the 3' side of the target guanine nucleotide. The HASL models derived from the analysis of 52 guanine-containing 4-mer sequences were used to highlight those atomic features in the favored TGCC sequence that were found most important in determining specificity. It was found that the NH2-O systems present in the two GC base pairs on the 3' side of the target guanine were significantly correlated to the degree of alkylation by uracil mustard. This finding is consistent with a prealkylation binding event occurring between these sites along the major groove and the uracil mustard O2/O4 system.

DNA sequence selectivity of guanine-N7 alkylation by nitrogen mustards is preserved in intact cells.

Nitrogen mustard alkylating agents react with isolated DNA in a sequence selective manner, and the substituent attached to the drug reactive group can impose a distinct sequence preference. It is not clear however to what extent the observed DNA sequence preferences are preserved in intact cells. The highly reiterated sequence of human alpha DNA has been used to determine the sites of guanine-N7 alkylation following treatment of cells with three nitrogen mustards, mechlorethamine, uracil mustard and quinacrine mustard, known to react in isolated DNA with distinctly different sequence preferences. Alpha DNA from drug treated cells was extracted, purified, end-labeled, and a 296 base pair, singly end-labelled, fragment isolated. Following the quantitative conversion of alkylation sites to strand breaks the fragments were separated on DNA sequencing gels. Clear differences were observed between the alkylation patterns of the three compounds, and the selectivities were qualitatively similar to those predicted and observed in the same sequence alkylated in vitro. In particular the unique preferences of uracil and quinacrine mustards for 5'-PyGC-3' and 5'-GT/GPu-3' sequences, respectively, were preserved in intact cells suggesting that the pattern of sequence dependent reactivity is not grossly affected by the nuclear milieu.

DNA cross-linking and sequence selectivity of aziridinylbenzoquinones: a unique reaction at 5'-GC-3' sequences with 2,5-diaziridinyl-1,4-benzoquinone upon reduction.

Several bifunctional alkylating agents of the aziridinylbenzoquinone class have been evaluated as potential antitumor agents. 3,6-Bis[(2-hydroxyethyl)amino]-2,5- diaziridinyl-1,4-benzoquinone (BZQ), 2,5-diaziridinyl-1,4-benzoquinone (DZQ), 3,6-bis(carboxyamino)-2,5-diaziridinyl- 1,4-benzoquinone (AZQ), and six analogues of AZQ have been studied for their ability to induce DNA interstrand cross-linking, as measured by an agarose gel technique, and to determine whether they react with DNA in a sequence-selective manner, as determined by a modified DNA sequencing technique. At an equimolar concentration (10 microM), only DZQ and BZQ showed any detectable cross-linking at pH 7 without reduction. Cross-linking was enhanced in both cases at low pH (4). Reduction by ascorbic acid at both pH's increased the cross-linking, which was particularly striking in the case of DZQ. In contrast, AZQ and its analogues only produced a significant level of cross-linking under both low-pH and reducing conditions, the extent of cross-linking decreasing as the size of the alkyl end group increased. The compounds reacted with all guanine-N7 positions in DNA with a sequence selectivity similar to other chemotherapeutic alkylating agents, such as the nitrogen mustards, although some small differences were observed with BZQ. Nonreduced DZQ showed a qualitatively similar pattern of reactivity to the other compounds, but on reduction (at pH 4 or 7) was found to react almost exclusively with 5'-GC-3' sequences, and in particular, at 5'-TGC-3' sites. A model to explain this unique reaction is proposed.

Comparative pharmacokinetics of DNA lesion formation and removal following treatment of L1210 cells with nitrogen mustards.

The kinetics of formation and removal of DNA interstrand crosslinks (ISC), DNA-protein crosslinks (DPC), and single strand breaks (SSB) by several nitrogen mustards were compared in order to determine the degree to which lesion selectivity may vary. The kinetic measurements using DNA alkaline elution methodology were obtained in mouse L1210 cells treated with mechlorethamine (HN2), phenylalanine mustard (L-PAM), uracil mustard (UM), 6-methyl-UM, and quinacrine mustard (QM). The ISC or DPC challenge delivered to cells was gauged on the basis of the kinetics as either total ISC or DPC produced, or as the area under the lesions versus time curve (AUC). By either measure (excepting QM), ISC correlated well with loss of colony survival, whereas DPC did not. The ISC/DPC ratio may therefore be a useful index of lesion selectivity. This ratio was significantly greater for 6-methyl-UM than for HN2. The ratio was also greater for L-PAM than for HN2 but only when gauged by AUC; this was attributable to an unusually slow rate for ISC removal in the case of L-PAM. The preferential reaction of UM at some 5'-GC-3' sites in purified DNA had suggested that UM might produce ISC with increased efficacy. UM, however, was somewhat less efficacious in ISC production than was 6-methyl-UM, which lacked selectivity for alkylation at 5'-GC-3'. QM was the only compound that produced detectable SSB, and the SSB were so numerous that ISC could not be quantitated.(ABSTRACT TRUNCATED AT 250 WORDS)