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PubMed1991

Efficacy of peptide bound m-L-sarcolysin (peptichemio) on melphalan resistant human myeloma cells in vitro.

Peptichemio (PTC) is a mixture of six synthetic oligopeptides, each containing the alkylating agent m-di(2-chloroethyl)amino-phenylalanine. Freshly obtained myeloma cell infiltrated human bone marrow specimens were in parallel exposed to melphalan and PTC. The cytotoxic effect of the drugs on the myeloma cells of each specimen was measured by the differential staining culture method (DISC). PTC displayed higher cytotoxicity to the myeloma cells as compared to melphalan in all 12 cases analysed. The increase of the cytotoxic effect of PTC compared to melphalan varied between different cases. In melphalan resistant cases the cytotoxic effect of PTC as compared to melphalan was clearly significant (P = 0.001).

Aged↗
PubMed1991

Interphase cell death as related to the cell cycle of melphalan-treated human myeloma cells.

The effect of melphalan on cell loss, cell growth and cell-cycle traverse was studied on the human myeloma cell line RPMI 8226. Melphalan treatment resulted in arrest of cells in late S- and G2-phases in a population of unsynchronized cells. At high concentrations of melphalan (e.g. 40 microM), cell loss was noticed during the first cell cycle after melphalan treatment in addition to the aforementioned arrest of cells in late S and G2. The cell loss after melphalan treatment was further analysed in cells enriched for G1-phase. Cell death in this population of cells occurred between 24 and 48 hr after treatment as the cells were in S and moving over to G2.

Cell Death↗
PubMed1999

Pharmacokinetics of melphalan in isolated limb perfusion.

The pharmacokinetics of melphalan was studied by sampling of tissue and plasma in 72 rats that underwent isolated hyperthermic limb perfusion under different conditions. A miniaturized extracorporeal circulation system for small animals was used for perfusion of the rat hindlimb. Melphalan levels (L-phenylalanine mustard, L-PAM) were determined by high-performance liquid chromatography (HPLC). The temperature of the perfusate plasma and tissue, pH, administration method, and flow rate were modified and compared with regard to their influence on pharmacokinetic parameters. The highest tissue penetration of melphalan was observed under the following conditions: (a) pH range of the perfusate plasma between 7.3 and 7.7 (physiological environment), (b) temperature range of the perfusate from 40 degrees to 41.5 degrees C (destruction of cellular carrier systems at higher temperatures and increased inactivation by hydrolysis of melphalan above 41.5 degrees C), (c) application of melphalan as a single dose into the reservoir of the extracorporeal circuit (optimal tissue penetration), and (d) reduced perfusate flow (prolonged contact time between perfusate and tissue).

Algorithms↗
PubMed2005

Oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients.

GOALS: The purpose of this study was to evaluate the efficacy of oral cryotherapy to prevent high-dose melphalan-induced stomatitis. PATIENTS AND METHODS: Eighteen consecutive recipients of allogeneic hematopoietic stem cell transplant conditioned with high-dose melphalan (140 mg/m2) in combination with fludarabine alone or with fludarabine and additional chemotherapy or radiation were enrolled. The severity of stomatitis was graded according to the National Cancer Institute Common Toxicity Criteria. Patients were kept on oral cryotherapy using ice chips and ice-cold water shortly before, during, and for additional 90 min after completion of melphalan administration. RESULTS: Only two of 18 patients (11.1%) developed grade 2 or 3 stomatitis while six of seven patients in the historical control developed it (85.7%; P=0.001). CONCLUSION: These results suggested that oral cryotherapy could effectively prevent stomatitis caused by high-dose melphalan, and we recommend that it should be incorporated into the conditioning regimen with high-dose melphalan.

Antineoplastic Agents, Alkylating↗
PubMed2006

Brief oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients.

We previously reported the efficacy of oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis. The purpose of this study was to evaluate whether the further shortening of the duration of oral cryotherapy could minimize its side effects while sparing its efficacy. Seventeen consecutive recipients of allogeneic hematopoieic stem cell transplant conditioned with high-dose melphalan in combination with fludarabine alone or with fludarabine and additional radiation were enrolled in the study. The severity of stomatitis was graded according to the National Cancer Institute-Common Toxicity Criteria. Patients were kept on oral cryotherapy shortly before, during, and for additional 30 min after the completion of melphalan administration (60-min oral cryotherapy). Patients who were also enrolled in our previous study received the same type of oral cryotherapy but for additional 90 min after the completion of melphalan administration (120-min oral cryotherapy), and they served as controls. Only 2 (11.8%) of 17 patients receiving 60-min oral cryotherapy and 2 (11.1%) of 18 patients receiving 120-min oral cryotherapy developed grade 2 or 3 stomatitis, respectively. The difference between groups was not statistically significant (P = 0.677). The incidence of unpleasant symptoms such as chills and nausea during oral cryotherapy decreased significantly with 60-min oral cryotherapy, as compared with that associated with 120-min oral cryotherapy (P < 0.01). These results suggest that 60-min oral cryotherapy is as effective as 120-min oral cryotherapy at preventing high-dose melphalan-induced stomatitis, and shorter treatment might have contributed to relieve patient discomfort during oral cryotherapy.

Administration, Oral↗
PubMed1992

Modulation of melphalan uptake in murine L5178Y lymphoblasts in vitro by changes in ionic environment.

The alkylating agent melphalan is actively transported in mammalian cells by two amino acid transport carriers: the sodium-dependent carrier with substrate preference for alanine-serine-cysteine (system ASC), and a sodium-independent carrier with preference for leucine (system L). The effect of altering the ionic environment of murine L5178Y lymphoblasts was investigated in order to determine not only the direct effects of hydrogen and calcium ions on these transport systems, but also the indirect effects of agents or modulators known to alter intracellular calcium. Melphalan transport followed a bell-shaped distribution curve over a pH range from 3 to 9 with a pH optimum of 4.3 and 4.6 for transport by systems ASC and L, respectively. Those agents that could cause a decrease in cytosolic calcium such as the calcium channel blockers verapamil, diltiazem and nitrendipine, the calcium chelator (ethyleneglycol-bis-(beta-aminoethylether) N,N,N',N'-tetraacetic acid (EGTA) and reduction of pH were found to augment melphalan uptake, whereas conditions that would elevate intracellular calcium such as the calcium ionophore A23187, the calcium channel agonist (-) Bay K 8644, elevation of extracellular calcium and the calcium pump inhibitor trifluoperazine were all found to decrease melphalan uptake. These findings suggest that modification of ionic environment directly or indirectly by agents known to alter intracellular calcium can modulate melphalan uptake.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1992

DNA sequence analysis of mutations induced by melphalan in the CHO aprt locus.

In previous work, we established that treatment with melphalan (L-phenylalanine mustard) produced a predominance of A.T-->T.A transversions in the Simian virus 40 (SV40)-based shuttle vector pZ189 during replication in human 293 cells. Mutations were induced with varying doses (4-12 microM) melphalan in the aprt gene of the hemizygous Chinese hamster ovary (CHO) cell line D422 to determine whether a similar mutation spectrum would be observed in an endogenous gene. DNA sequence alterations were determined for 39 spontaneous and 41 melphalan-induced independent mutant clones. Other than a predominance of transversions in both systems, the spectrum of melphalan-induced aprt mutations bears little resemblance to the spectrum observed in the supF gene of the shuttle plasmid pZ189. In aprt, mutations at G.C base pairs (bp) predominated (29 of 41 base substitutions). Significantly enhanced mutagenesis was observed at 5' G-G-C 3' and 5' G-G-C-C 3' sites in the aprt gene. Almost half of the melphalan-induced base substitutions occurred at 5' G-N-C 3' sequences, which are believed to be potential interstrand crosslink sites.

Adenine Phosphoribosyltransferase↗
PubMed1982

Pharmacokinetics of oral and intravenous melphalan during routine treatment of multiple myeloma.

Plasma melphalan levels have been measured in nine (mostly stage IIIA) multiple myeloma patients after therapeutic doses of drug had been given p.o. and i.v. A new isocratic high-pressure liquid chromatographic (HPLC) method with a sensitivity limit o 5 ng/ml was used to quantify the melphalan. Patients receiving 8-28.5 mg melphalan i.v. showed alpha and beta plasma decays with half-lives of 7.7 +/- 3.3 (mean +/- S.D.) and 83 +/- 14 min respectively. The apparent volume of the central compartment was 12.8 +/- 4.3 1, and the total volume of distribution was 0.62 +/- 0.21 l/kg. Very variable absorption was seen in the same patients after receiving 5-12 mg melphalan p.o. The half-life of the absorption phase varied from 2.1 to 62.1 min (22.8 +/- 18.1 min) with delays (before absorption started) of 0-113 min. The fraction of dose absorbed varied from 0.32 to 1.03 (0.72 +/- 0.23), and the half-life of the beta phase was 92 +/- 27 min. The type of breakfast eaten before p.o. melphalan was found to correlate with the fraction of drug absorbed.

Administration, Oral↗
PubMed1990

Oral dosage of melphalan and response to treatment in multiple myeloma.

Forty-nine consecutive patients with multiple myeloma were analysed for treatment response in relation to dose of orally administered melphalan (induction therapy). All patients were given at least six courses of melphalan-prednisone. Treatment response, defined as a reduction of the myeloma protein of greater than 50%, was seen in 26 patients while 23 were non-responders. When treatment response was related to the dosage of melphalan given by mg/kg of body weight, the numbers of responding and non-responding patients were similar in the group of patients without dose reduction as well as in that with dose reduction. Drug-induced suppression of white blood cell and platelet count was similar in the responding as well as in the non-responding group indicating that the reason for non-response is not simply explained by deficient drug absorption. When the cumulative dose of melphalan given during the induction therapy was analysed, however, a positive correlation (r = 0.47, P less than 0.001) was seen between the cumulative dose and the degree of response. Thus, the cumulative dose of melphalan given during induction therapy seems to be of importance for the response, but other factors as intrinsic differences in cell sensitivity may also explain the individual responsiveness.

Administration, Oral↗
PubMed1986

In vivo modulation of glutathione by buthionine sulfoximine: effect on marrow response to melphalan.

The effect of giving buthionine sulfoximine (BSO), 0.0265 g/mouse (6 mM), at 12 and 6 hr before treatment with melphalan--0.0 mg, 3 mg, 6 mg, and 9 mg/kg, was studied in C3H mice, and was compared with control groups that received normal saline 12 and 6 hr before identical melphalan treatment. BSO treatment resulted in depletion of GSH levels in bone marrow, liver, and muscle to 65, 13, and 41% of control levels, respectively. Hematological toxicity was assessed by measurement of CFU-S survival and peripheral white cell counts. CFU-S survival decreased with increasing doses of melphalan, but no difference was observed with BSO pre-treatment. Likewise, WBC counts following melphalan 9 mg/kg, were similar irrespective of BSO pre-treatment. These data suggest that the marrow toxicity seen with melphalan is not worsened by pre-treatment with BSO and that if tumors can be pre-sensitized with BSO, there may be a clinical role for melphalan/BSO drug combination.

Animals↗
PubMed1989

Potentiation of the tumor cytotoxicity of melphalan by vasodilating drugs.

Previous studies have shown that several vasoactive drugs can selectively reduce blood flow and increase hypoxia in experimental tumor systems. Our studies with one such agent, the vasodilator hydralazine, have clearly demonstrated that it can increase the tumor cytotoxicity of drugs which are known to be more toxic under hypoxic conditions. We have now extended our investigations to determine whether such selective reductions in tumor blood flow induced by hydralazine can increase the tumor cytotoxicity of other classes of cancer chemotherapeutic drugs. Our initial studies have involved the alkylating agent melphalan. Administration of hydralazine (5 mg/kg IP) at various times before or after melphalan results in increased tumor cytotoxicity in the Lewis lung carcinoma. An enhancement factor of between 2 and 3 was obtained in this tumor system. Similar results are observed if the vasodilator cadralazine is used. In contrast to the enhancement of the tumor cytotoxicity of melphalan by hydralazine, systemic toxicity is only increased by a factor of 1.2. Therefore, therapeutic gain may accrue from the use of vasodilating agents in combination with melphalan. Studies using spheroids to establish the mechanism responsible for the enhanced tumor cytotoxicity indicate that both hypoxia and pH can influence melphalan toxicity.

Animals↗
PubMed1992

Melphalan concentration and distribution in the tissues of tumour-bearing limbs treated by isolated limb perfusion.

Levels of melphalan (L-phenylalanine mustard) were measured in the tissues of tumour-bearing limbs treated by isolated limb perfusion (ILP). 41 samples of melanoma tissue, normal fat and skin were excised from 15 patients during ILP. A high performance liquid chromatography assay was used to measure melphalan concentrations. Levels of melphalan were higher in tumour than in fat (P < 0.01, Wilcoxon signed-ranks test), and not significantly different from levels in adjacent skin. In 2 cases there was significant regional toxicity in the treated limb, but this was not related to the levels of melphalan measured in the tissues of the limb. It is encouraging that the concentrations of melphalan which were achieved in large necrotic nodules by ILP were similar to those in well-perfused normal skin.

Adipose Tissue↗
PubMed1983

Controlled trial of adjuvant chemotherapy with melphalan for breast cancer.

370 patients who had carcinoma of the breast with involved axillary lymph-nodes were randomised after total mastectomy and axillary clearance to receive either no additional treatment or melphalan 6 mg/m2 daily for 5 days every 6 weeks for sixteen cycles. There was a trend towards longer relapse-free survival (RFS) in patients treated with melphalan, but this was not significant either in the whole series or in sub-groups according to menopausal status or extent of nodal involvement. In patients receiving melphalan RFS was not significantly affected by either the occurrence of amenorrhoea or the dosage of melphalan received. Overall survival did not differ significantly between the two groups. The results of this trial suggest that there is no place for the use of melphalan as adjuvant therapy in the management of early breast cancer.

Adult↗
PubMed1997

Sensitivity of melphalan-resistant tumors to selenite in vivo.

Previous studies have demonstrated that melphalan-resistant human ovarian tumor cells exhibit a higher degree of sensitivity to the cytotoxic effects of selenite in vitro than comparable drug-sensitive cells (P.B. Caffrey, G.D. Frenkel, Selenite cytotoxicity in drug resistant and non-resistant human ovarian tumor cells, Cancer Res. 52 (1992) 4812-4816; P.B. Caffrey, G.D. Frenkel, The development of drug resistance by tumor cells in vitro is accompanied by the development of sensitivity to selenite, Cancer Lett. 81 (1994) 59-65). We have now examined the sensitivity of drug-resistant tumors to selenite in vivo. A2780 human ovarian tumor cells, or their melphalan-resistant derivative (A2780ME) cells were injected subcutaneously into nude mice and the resulting tumors were found to be melphalan-sensitive and -resistant, respectively, in vivo. Treatment with selenite (2 mg/kg Se s.c.), which had no overt toxic effect on the animals, resulted in a significant decrease in the rate of growth of the melphalan-resistant tumors, but not on the rate of growth of the drug-sensitive tumors. Thus, melphalan-resistant ovarian tumors are also more sensitive to selenite treatment in vivo.

Animals↗
PubMed2000

Comparison between capillary and nano liquid chromatography-electrospray mass spectrometry for the analysis of minor DNA-melphalan adducts.

Nano liquid chromatography (nanoLC) coupled to electrospray mass spectrometry (ES-MS) was evaluated for the analysis of DNA adducts in melphalan-treated Jurkat cells. The detection limit of the nanoLC-ES-MS-MS system was assessed using a dAMP-melphalan adduct. Compared to capillary liquid chromatography (capLC) ES-MS the absolute detection limit could be improved by a factor 10, leading to the detection of 395 fg dAMP-melphalan adduct under single-ion monitoring conditions at a S/N of 14. Minor adducts such as cross-linked adducts could be detected in in vitro solutions of 2'-deoxynucleotides (dNMP) treated with melphalan using column-switching nanoLC-ES-MS. These adducts were not found using capLC-ES-MS. More detailed structural information of the alkylation sites was obtained by examining the nanoLC-ES-MS-MS data. Jurkat cells were treated with melphalan, the modified DNA was isolated and enzymatically hydrolyzed. Several modified dinucleotides were identified, the most abundant adducts were pdG(Mel(Cl))pdC (m/z=453, t(r)=17.0 min) and pdG(Mel(OH)) pdC ring opened (m/z=453, t(r)=39.5 min).

Animals↗
PubMed1999

A stability-indicating method for the determination of melphalan and related impurity content by gradient HPLC.

A robust gradient high performance liquid chromatographic (HPLC) procedure is described for the simultaneous determination of melphalan content and related impurities in melphalan drug substance. The sample solution is prepared in methanol and injected. A linear gradient from 5 to 60% acetonitrile in water containing 0.05% v/v acetic acid, 0.01% v/v triethylamine, and 0.05% w/v ammonium acetate is applied over 20 min. The chromatographic conditions are capable of separating and quantifying all impurities found in routine production batches of melphalan at above 0.1% area/area. The method has been fully validated and is linear over the column loading range of 0-3 microg of melphalan. All related impurities occurring in routine batches at above 0.1% area/area have been identified, and structures assigned. The method has been applied to melphalan samples stored under stressed conditions, and shown to be stability-indicating.

Buffers↗
PubMedDate not supplied

Synthesis and in vivo biodisposition of [14C]-quaternary ammonium-melphalan conjugate, a potential cartilage-targeted alkylating drug.

For the purpose of developing more selective anticancer drugs that would concentrate in the malignant cartilaginous tumors (chondrosarcomas), and so improve therapeutic index through a reduction of side effects, a quaternary ammonium (QA) conjugate of melphalan was synthesized and labeled with (14)C by linking the QA moiety to nitrogen mustard via an amide bond. Comparative pharmacokinetic study of [(14)C]-melphalan and its [(14)C]-QA conjugate conducted on rats showed that the two compounds were principally excreted by the urinary way. The blood elimination of the QA conjugate was faster than that of the melphalan. In the other hand a higher rate of radioactivity derived of [(14)C]-MQA was found in feces. In the biodisposition for most organs, no striking differences were found between melphalan and its QA conjugate except for cartilages which exhibited more higher radioactivity level. Amounts of radioactivity derived from [(14)C]-QA conjugates measured in cartilaginous tissues until 1 h after injection demonstrate that the introduction of a QA moiety on melphalan allows the molecule to be carried selectively to cartilaginous tissues. As the [(14)C]-QA conjugate is radiolabeled on the chloroethyl alkylating moiety, levels of radioactivity measured in the cartilaginous tissues results from unchanged compound or metabolite having kept the active group.

Animals↗
PubMed1978

Effect of high-dose melphalan on marrow and intestinal epithelium in mice pretreated with cyclophosphamide.

The lethal effect of high-dose melphalan in mice could be offset by pretreatment with cyclophosphamide, cytosine arabinoside or low-dose melphalan. The reason for improved survival is unclear. Althoug animals given high-dose melphalan died with symptoms of gut death, in only one instance, that with low-dose melphalan itself, did pretreatment protect the intestinal epithelium as measured by the microcolony assay. A small enhancement in the recovery of the haemopoietic tissue in pretreated animals was noted, although this on its own is unlikely to explain the phenomenon. Experiments in tumour-bearing mice showed that pretreatment with cyclophosphamide did not reduce the toxicity of melphalan to the Lewis lung carcinoma.

Animals↗