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PubMed1987

Immunological detection of DNA damage caused by melphalan using monoclonal antibodies.

Immunological detection of melphalan adducts on DNA should permit new types of clinical and experimental investigations. Five cloned rat hybridoma cell lines were derived, each producing an antibody that bound to DNA alkylated with melphalan (phenylalanine mustard) but not to normal DNA. Further characterization of one melphalan specific antibody (MP5/73) used a competitive fluorogenic enzyme-linked immunoabsorbent assay. Using denatured DNA, 50% inhibition of antibody binding was caused by 30 fmol of total melphalan adducts (determined using radioactive melphalan) per assay well. Denatured control DNA caused 16 to 24% inhibition at 45 micrograms (130 nmol)/well, the maximum concentration tested. Adducts on RNA behaved similarly to those on denatured DNA. Adducts on native DNA caused 50% inhibition at 272 to 1335 fmol/well dependent upon alkylation frequency and sonication treatment. Native control DNA caused no detectable inhibition at 45 micrograms/well. The adducts recognized by the antibody were thermo- and alkali labile. Denaturation of the alkylated DNA by moderate heating in the presence of 75% formamide gave 50% inhibition at 50 fmol/well, indicating that only 5% of the recognized adducts could bind antibody in native DNA.

Animals↗
PubMed1985

Development of resistance to MOPC-315 plasmacytoma after intralesional and intraperitoneal melphalan therapy of tumor-bearing BALB/c mice. II. Enhancement of in vitro cell-mediated cytotoxicity by combined chemotherapy-immunotherapy.

As previously reported, tumor-bearing BALB/c mice can be cured by split-course melphalan therapy, with 40-60% of the treated animals developing resistance to subsequent challenge with viable MOPC-315. The present study deals with the identification of effector-cytotoxic cells that may be developed as a result of chemotherapy-induced tumor regression and their possible potentiation by active, specific immunization with melphalan- and glutaraldehyde-treated MOPC-315 plasmacytoma cells. The cytotoxic potential of spleen-derived lymphocytes in treated animals could be demonstrated only after in vitro sensitization against mitomycin-treated MOPC-315 cells. Lymphocyte-mediated cytotoxicity, as measured against syngeneic 51Cr-labeled MOPC-315, could be detected in melphalan-cured animals and was significantly enhanced by active immunization as compared to the cytotoxicity seen in normal and tumor-bearing mice. With the use of M109 syngeneic, unrelated tumor cells as control targets in the assay, no cytotoxicity was detected. Macrophage cytotoxicity was not significantly enhanced in any of the treatment groups described, with these assays performed 6-8 weeks following treatment and cure. When in vitro killing of MOPC-315 targets was tested with the use of peritoneal macrophages harvested shortly following cure of ascitic tumor by ip injected melphalan, the cytotoxic response was significantly enhanced. In conclusion, following chemotherapy-mediated cure of established MOPC-315 tumors, splenic lymphocytes exhibited enhanced antitumor cytotoxicity, which was further augmented by active immunization. Macrophage activation, as measured by direct cytotoxicity against MOPC-315 targets, was found to occur locally and early following the event of melphalan-induced tumor regression.

Animals↗
PubMed1984

High dose melphalan with autologous marrow rescue in cancer treatment.

Autologous bone marrow rescue circumvents the major toxicity of most cancer chemotherapeutic agents. Melphalan is a particularly well suited agent for use with autologous bone marrow rescue and produces response in chemo-resistant tumours. Thirteen patients have been treated with high dose melphalan with autologous bone marrow rescue in this department. The aims of treatment were palliation, debulking of non-resectable tumours and curative adjuvant therapy. Three patients died of melphalan related toxicity. Of the remaining ten patients there were five partial remissions, one objective response, one complete remission, one with no response and two patients in whom the response is not yet assessable (adjuvant therapy). In our experience high dose melphalan is an effective means of killing tumour cells which are not sensitive to chemotherapy at conventional doses. It is recommended in young patients who have not had extensive previous radio- or chemotherapy, in the early stages of disease, with cure or prolonged remission the aim. High dose melphalan is not recommended in the older patient or in those with massive diseases and is no longer used with palliative intent.

Adenocarcinoma↗
PubMed1982

Effect of melphalan on delta-aminolevulinic acid synthetase in the spleen, bone marrow and liver of rats.

The effect of melphalan, an antineoplastic alkylating agent, on the activity of delta-aminolevulinic acid synthetase (ALA-S) was studied. When given in a single oral dose (20 mg/kg) to male rats. ALA-S activity in the spleen rapidly declined, reaching 9% of controls 7 days after administration. A return to control values occurred after 10 days, followed by a rebound increase in activity to 180% of controls at day 15. After melphalan administration, a gradual loss in spleen weight was observed until day 10, followed by a rebound increase in spleen weight at day 15. Spleen heme oxygenase activity was induced to 243% of controls 7 days after melphalan administration. However, by 20 days the activity was only 55% above controls. Bone marrow ALA-S activity declined to 38% of controls 3 days after treatment, followed by a return to controls after 7 days. The return to control values at day 15 was accompanied by a shift in the differential white blood cell count to the segmented form. Red blood cell counts and hemoglobin content were decreased to 77% of controls at day 7. Liver ALA-S was not appreciably affected by melphalan except for a decrease to 56% of controls at day 7. It is concluded that melphalan depresses the level of activity of the erythroid form of ALA-S in spleen and bone marrow but has less effect upon the level of activity of the nonerythroid form in the liver.

5-Aminolevulinate Synthetase↗
PubMedDate not supplied

Uptake of melphalan by human ovarian carcinoma cells and its relationship to the amino acid content of ascitic fluid.

Melphalan uptake by human ovarian carcinoma cells obtained from patients with clinically documented disease was significantly reduced by ascitic fluid. Examination of the ascitic fluid revealed physiologic concentrations of a number of amino acids, notably leucine (100-150 microM) and glutamine (500-600 microM). These two amino acids, when used at concentrations found in the ascitic fluid, significantly reduced melphalan uptake to levels which approximated those obtained with ascitic fluid. The possible effect of high concentrations of these amino acids on melphalan therapy for this neoplasm is discussed with particular reference to the model melphalan transport system in the murine L1210 leukemia cell. Specific emphasis is placed on the rationale for combining melphalan with arginine and a glutamine-depleting enzyme.

Adenocarcinoma, Papillary↗
PubMedDate not supplied

The cytotoxicity of melphalan and its relationship to pH, hypoxia and drug uptake.

In the present in vitro studies we examined the effect of hypoxia and acidic pH, two important consequences of reduced blood flow in vivo, on the cytotoxicity of melphalan treatment in Chinese hamster V79-WNRE and SiHa human tumor cells. Cells were exposed to various concentrations of melphalan for 1 hr at 37 degrees C under oxic or hypoxic conditions; pH 6.6 or 7.4, and cell survival was measured. The cytotoxicity of melphalan was potentiated by both low pH and hypoxia, in both cell lines. The overall potentiation, expressed as an enhancement ratio (ER), from both hypoxia and low pH was 3.5 in V79-WNRE and 2.9 in SiHa cells. The potentiation of cell killing produced by hypoxia alone (ERHyp) ranged from 1.4 to 1.9, and was greater in V79-WNRE than in SiHa cells. The potentiation from low pH (ERpH) was approximately 2 in both cell lines. HPLC analysis showed substantial intracellular accumulation of melphalan in both cell lines. Hypoxia and reduced pH further enhanced uptake of melphalan but this was not sufficient by itself to account for the increased potentiation of cytotoxicity observed under those conditions.

Animals↗
PubMed1996

Low-dose melphalan for treatment of high-risk myelodysplastic syndromes.

Twenty-one consecutive patients with high-risk myelodysplastic syndromes (MDS) including six with refractory anemia with excess blasts (RAEB) and 15 with RAEB in transformation (RAEBt) were treated with daily oral low-dose melphalan (2 mg/day). Seven patients achieved complete remission (CR), one patient partial response, and four minor response while the remaining eight did not respond. The median age of the patients was 65 (range 56-83 years). The mean total amount of melphalan given was 140+/-19 mg in patients who achieved CR. The median duration of CR was 14.5 months. Serious toxicity was not encountered in any of the cases. Neither marrow suppression nor pancytopenia was observed during the administration of melphalan in patients who achieved CR. The clinical features of CR patients included normal karyotype and hypocellular marrow in biopsied specimen from the lilac bone. These observations suggest that melphalan may exert some differentiation effects on leukemic cells in addition to cytotoxic effects. Our study indicates that daily administration of low-dose melphalan is worth trying in the treatment of elderly patients with high-risk MDS.

Aged↗
PubMed1996

Effects of hyperthermic isolated limb perfusion with recombinant tumor necrosis factor alpha and melphalan on the human fibrinolytic system.

This study was undertaken to determine the effects on systemic fibrinolysis of hyperthermic isolated limb perfusion with recombinant tumor necrosis factor alpha (r-TNF-alpha) and melphalan, with or without pretreatment with recombinant IFN-gamma (r-IFN-gamma). Twenty patients were treated with r-TNF-alpha and melphalan; four patients, treated with melphalan only, served as controls. Of the twenty patients treated with both r-TNF-alpha and melphalan, eight received r-IFN-gamma for two days before the perfusion and as a bolus into the perfusion circuit. A significant leak of r-TNF-alpha from the perfusion circuit to the systemic circulation was observed in all r-TNF-alpha-treated patients (mean maximum TNF-alpha, 87,227 ng/liter versus 31 ng/liter in controls; P < 0.002). In these patients, but not in controls, there was an almost instantaneous rise in systemic tissue plasminogen activator activity (from 0.26 to 5.28 IU/ml in 90 min), causing activation of fibrinolysis. After a delay of 90 min, plasminogen activator inhibitor-1 (PAI-1) antigen rose to high levels in the r-TNF-alpha-treated group (mean maximum PAI-1, 1652 ng/ml versus 211 ng/ml in controls; P < 0.02), associated with a sharp decrease of tissue plasminogen activator activity and a slower decrease of plasminogen-antiplasminogen complexes (from 5.28 to 0.02 IU/ml in 2 h and from 1573 to 347 micrograms/liter in 22 h, respectively). No additional effect of IFN-gamma pretreatment on fibrinolysis could be demonstrated. These results suggest that in isolated limb perfusion with r-TNF-alpha and melphalan an initial activation of systemic fibrinolysis, induced by leakage of r-TNF-alpha from the perfusion circuit, is set off by a subsequent inhibition of the fibrinolytic system by PAI-1. This large increase in PAI-1 could place the patient at risk for deposition of microthrombi in the systemic circulation.

Antineoplastic Agents↗
PubMed1997

Fibrinolytic and coagulant responses to regional limb perfusions of tumor necrosis factor, interferon-gamma, and/or melphalan.

Regional limb perfusion with antineoplastic agents stresses the local vasculature in a variety of ways. However, by monitoring the perfusates from limbs treated with melphalan alone or with melphalan plus tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma), we were able to distinguish the effect of the cytokines on the observed coagulant and fibrinolytic responses. We collected samples of effluent from a series of lower extremities that were perfused with the cytokines and/or melphalan as treatment for localized melanoma. Both regimens produced statistically significant evidence of coagulant and fibrinolytic activation. However, limbs receiving cytokines in addition to the melphalan responded with a sharper rise in tissue plasminogen activator (tPA) and plasmin (plasmin-antiplasmin complexes [PAP]) than limbs treated with melphalan alone. Evidence of thrombin formation (prothrombin fragment 1 + 2 [F1 + 2], thrombin-antithrombin complexes [TAT]) was also greater when the cytokines were included, although the response was delayed and less consistent than the fibrinolytic activation.

Adult↗
PubMed1998

Monofunctional adenine N-3 adducts of melphalan: occurrence at a mutational hotspot sequence and resistance to removal by AlkA protein.

Previous work showed that a CTAAA sequence in the supF gene of the shuttle plasmid pZ189 was a hotspot for mutagenesis by the aromatic nitrogen mustards melphalan and chlorambucil, and indirect evidence suggested adenine N-3 adducts as premutagenic lesions. In order to characterize the adducts formed at this sequence more directly, a substrate was prepared in which the three adjacent adenines in the CTAAA sequence were 3H-labeled. Following treatment of this substrate with [14C]melphalan, thermolabile adducts were depurinated and analyzed by HPLC. Only a single peak bearing both 3H and 14C label was detected and it coeluted with the single major adduct formed by the reaction of melphalan with free adenine base. Various spectrometric analyses of this species were all consistent with its identification as a monofunctional adenine N-3 adduct of melphalan. There was no evidence for any bifunctional adducts involving the labeled adenines. There was little if any release of the adenine N-3 adduct of melphalan by Escherichia coli AlkA protein, under conditions where 3-methyladenine was quantitatively released. The results support the proposal that monofunctional adenine N-3 adducts are intermediates in the generation of A.T-->T.A and A.T-->C.G transversions by aromatic nitrogen mustards.

Base Sequence↗
PubMed1979

Dacarbazine and melphalan. Enhancement by dosage scheduling of the effect in combination treatment on the Harding-Passey melanoma in C3D2F1 mice.

The best combination and schedule for dacarbazine and melphalan with the Harding-Passey melanoma in C3D2F1 mice is achieved when dacarbazine is administered first, followed by melphalan, given on either the day of dacarbazine therapy or the first three days after dacarbazine is given. When dacarbazine is given first, followed by melphalan on day 0, 1, 2, or 3, the effect of the two drugs is considerably more than additive. Other schedules reduce the outcome to a simple additive effect, or to an outcome that is less than additive, in which the combination is less effective than melphalan used alone. The effect of variations in the order and schedule of drug administration should be investigated in future trials of cancer chemotherapeutic agents, since profound effects may occur with these variations.

Animals↗
PubMed1997

High dose tumor necrosis factor-alpha and melphalan administered via isolated limb perfusion for advanced limb soft tissue sarcoma results in a >90% response rate and limb preservation.

BACKGROUND: Recombinant tumor necrosis factor-alpha (rTNF-alpha) is a highly potential antineoplastic agent. However, its systemic administration in humans has resulted in a life-threatening septic shock-like syndrome, and its use has been abandoned. The administration of high dose rTNF-alpha and melphalan via isolated limb perfusion (ILP) eliminated the systemic side effects and was shown to be very effective for metastatic melanoma confined to the limb. The purpose of the current study was to assess the role of rTNF-alpha and melphalan administered via ILP in patients with soft tissue sarcoma. Amputation is unavoidable in 10% of these patients despite aggressive conventional therapy. Limb preservation was the objective in this select group of candidates for amputation or mutilating surgery. METHODS: During a 36-month period, 35 patients with high grade soft tissue sarcoma underwent 41 ILPs with high dose rTNF-alpha (3-4 mg) and melphalan (1-1.5 mg/kg). There were 21 males and 14 females. The mean age was 48 years (range, 14-80 years). Histologic subtypes included malignant fibrous histiocytoma, synovial, liposarcoma, malignant schwannoma, desmoid, clear cell, epithelioid, rhabdomyosarcoma, leiomyosarcoma, and unclassifiable. Twenty-one patients presented with recurrent and 14 with very extensive primary tumors. The tumors were located in the upper extremity in 8 patients and in the lower extremity in 27 patients. Twenty-five patients were candidates for amputation and 10 for extensive mutilating surgery. ILP was performed via the corresponding vessels proximal to the tumor. Six patients with partial response (PR) insufficient to render them resectable underwent a second ILP. With the exception of 4 of 9 patients with multifocal lesions and 1 who refused surgery, resection of the residual tumor or tumor bed or limb was performed 6-8 weeks after ILP. RESULTS: Marked tumor softening occurred within 48 hours, and in tumors protruding through the skin hemorrhagic necrosis was evident within 24 hours. The overall response rate was 91%. Thirteen patients (37%) had a complete response and 19 (54%) had a PR; in 5 of these patients > 90% necrosis of the tumor occurred. In 3 patients (8.5%), only minimal regression was observed (stabilization of disease). The rate of limb sparing was 85% (29 of 34 patients). CONCLUSIONS: The combination of high dose rTNF-alpha and melphalan given via ILP appears to be effective in patients with advanced soft tissue sarcoma confined to the limb, achieving a high response rate and limb preservation.

Adolescent↗
PubMed1982

Comparison of oral melphalan, CCNU, and BCNU with and without vincristine and prednisone in the treatment of multiple myeloma. Cancer and Leukemia Group B experience.

A total of 361 evaluable patients with previously untreated multiple myeloma were randomized to receive oral melphalan (0.15 mg/kg/day for seven days, followed by 0.05 mg/kg/day after recovery from the nadir of the leukocytes), BCNU (150 mg/m2 intravenously every six weeks) or CCNU (100 mg/m2 orally every six weeks). All patients received a tapering six-weeks) or CCNU (100 mg/m2 orally every six weeks). All patients received a tapering six-week course of prednisone starting at 0.8 mg/kg for the first two weeks. At week 22, one-half of the patients were randomized to receive vincristine (1 mg/m2) and prednisone (0.6 mg/kg for seven days) every two months in addition to previous therapy. The melphalan treated patients showed a significantly higher overall objective response frequency (59%), according to Myeloma Task Force criteria, when compared to those treated with BCNU (40%) or CCNU (42%). The survivals for all patients were not statistically different for the three treatment programs. However, the good-risk patients treated with melphalan had significantly longer survival (P = 0.02) than the equivalent patients who received BCNU or CCNU. The addition of vincristine and prednisone at week 2 did not significantly increase the percentage of subsequent objective responses or prolong the subsequent survival of any treatment group. It is concluded that oral melphalan is superior to BCNU and CCNU in producing objective responses and in prolonging survival in good risk patients.

Antineoplastic Agents↗
PubMed1979

Kinetics of intravenous melphalan.

We have studied the disposition and elimination of melphalan after intravenous administration in 9 patients with cancer. High-pressure liquid chromatography and 14C-melphalan were used to assay drug concentration in plasma and urine. Composite plasma t1/2alpha was 7.7 +/- 3.3 and t1/2beta was 108 +/- 20.8 min for 8 of the patients. The mean 24-hr urinary excretion of melphalan was 13.0 +/- 5.4% of the administered dose. In 2 patients, 80% to 100% of the measured 14C counts in plasma and urine samples at each study interval, up to 24 hr after drug administration, could be accounted for by the sum of parent compound, monohydroxy and dihydroxy products, and methanol nonextractable radioactivity (i.e., protein-bound activity). These data and evidence of rapid disappearance from plasma at 37 degrees in vitro suggest that spontaneous degradation, and not enzymatic metabolism, is the major determinant of the t1/2 of melphalan in vivo.

Adult↗
PubMed1994

Receptor-mediated cytotoxicity of alpha-MSH fragments containing melphalan in a human melanoma cell line.

Four alpha-MSH drug conjugates have been synthesized, 2 C-terminal (Pep 3 and 4) and 2 central fragments (Pep 1 and 2), the latter being the 4-10 sequence known to be the main alpha-MSH-receptor-recognition site. Melphalan was introduced into each sequence at different locations. Their ability to recognize alpha-MSH receptors as well as their cytotoxic effects were compared in 3 cell lines: melanoma, carcinoma and fibroblast cells. Pep 1 and 2 were able to specifically bind to MSH receptors on melanoma cells by displacing labelled alpha-MSH from its binding sites at concentrations similar to the 4-10 heptapeptide sequence known to contain the main receptor-recognition site. They subsequently penetrate the cell, most probably by a receptor internalization mechanism, since about half of their effect could be inhibited by competition at the receptor level. Significant and selective cytotoxic effects to melanoma cells could be observed after only 2 hr exposure to the drug conjugates. Interestingly, these 2 conjugates, differing only in melphalan position, showed completely different cytotoxicity in terms of IC50 values, Pep 1 being 24 times more toxic to all cells; but the 2 were equally specific to melanoma cells. However, they both were less toxic to all cells than melphalan itself. Furthermore, Pep 1 and 2 were able to block the receptor and, unlike Pep 3 and 4, their cytotoxic effect could be significantly inhibited by an alpha-MSH agonist. Pep 3 and 4 were 5 to 10 times less toxic than melphalan to melanoma and carcinoma cells and 50 times less to fibroblast cells, and did not show any cell-type selectivity. They were less toxic than Pep 1 to melanoma and carcinoma cells by a factor of 2, but equally toxic to fibroblasts. In contrast, they were more toxic than Pep 2 to fibroblasts, melanoma and carcinoma by a factor of 3, 10 and 24 respectively. Our data strongly suggest a receptor-mediated cytotoxicity mechanism occurring with alpha-MSH central fragments in human melanoma cells due to the presence of alpha-MSH-specific receptors. This mechanism appeared to be both peptide- and cell-type-specific.

Carcinoma, Squamous Cell↗
PubMed1995

Rapid increase in plasma tenascin-C concentration after isolated limb perfusion with high-dose tumor necrosis factor (TNF), interferon gamma (IFN gamma) and melphalan for regionally advanced tumors.

The matrix protein tenascin-C (TN-C) is present in the blood of healthy individuals at concentrations around 1 mg/l. Elevated serum levels have been reported in cancer patients. In this study we have measured the concentration of circulating TN-C in 40 patients with melanoma, soft-tissue sarcoma (STS) or squamous-cell carcinoma (SCC) of the limbs, and have found a minor increase in the mean concentration compared with healthy subjects. Only 10 patients had TN-C levels above the normal range. No correlation was observed between TN-C levels and tumor burden. Nineteen patients were treated by isolation limb perfusion (ILP) with TNF, IFN gamma, melphalan (11 melanoma, 2 SCC and I STS), melphalan alone (3 melanoma) or hyperthermia at 41.5 degrees C (2 melanoma). ILP with TNF, IFN gamma and melphalan induced a rapid increase in plasma TN-C levels, peaking in most patients between 24 or 48 hr after ILP. Two patients treated with hyperthermia only had a slow increase in TN-C concentration peaking at day 4, while the patients treated with melphalan alone had no significant change. In some cases elevated TN-C levels persisted for over 8 weeks after ILP. The early rise in TN-C concentration correlates with the increase in circulating C-reactive protein. Our findings suggest that circulating TN-C behaves, at least in part, as an acute-phase protein and that it may play a role in the inflammatory response.

Adult↗
PubMed1987

Zinc-induced reduction in melphalan cytotoxicity: heterogeneity of response of cloned human tumor cells.

Previous studies with cultured human normal fibroblasts indicated that pretreatment of the cells with zinc for 12 h prior to exposure to the alkylating agent melphalan increased survival by seven- to ninefold over survival values obtained in cultures treated with drug only. Comparable pretreatment of cells derived from a variety of human tumors resulted in an increase in survival of 1.7-fold or less. To determine whether the limited responsiveness to zinc represented a general property of tumor cells (which would be characterized by a lack of highly zinc-responsive subpopulations contained within the parental tumor populations), a series of clones was prepared from the A101D human melanoma line and the A549 human alveolar cell carcinoma line. Cells from each clone were then challenged with melphalan with and without zinc pretreatment. Twenty-five percent of the tumor clones exhibited increased resistance to melphalan following pretreatment with zinc (range of 2.1- to 5.2-fold increase in survival), indicating that the parental tumor lines were highly heterogenous in regard to inducibility to a state of reduced sensitivity to melphalan. There was no evidence of a relationship between zinc-induced reductions in toxicity and induced elevations in total intracellular glutathione content, indicating that the primary effect of zinc is not directed toward elevating intracellular levels of glutathione.

Cell Survival↗
PubMed2006

Quantitative determination of melphalan DNA adducts using HPLC - inductively coupled mass spectrometry.

For the quantification of Melphalan DNA adducts, an analytical approach based on the detection of phosphorus using liquid chromatography combined with inductively-coupled-plasma mass spectrometry (ICP-MS) was developed. In reaction mixtures of native 2'-deoxynucleotides-5'-monophosphates and Melphalan, which were separated using reversed phase chromatography, phosphate adducts were found as the most abundant modifications. Besides the phosphate adducts, several base alkylated adducts were observed. In calf thymus DNA incubated with Melphalan and enzymatically digested using Nuclease P1, the phosphate adducts as well as monoalkylated dinucleotides were found. The most abundant single Melphalan adduct observed in DNA was a ring-opened adenosine monophosphate. Some dinucleotide adducts and the adenosine adduct were identified using electrospray ionization mass spectrometry (ESI-MS).

Algorithms↗