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PubMedDate not supplied

Pharmacokinetics of high-dose intravenous melphalan in patients undergoing peripheral blood hematopoietic progenitor-cell transplantation.

The pharmacokinetics of melphalan following high-dose (140 mg/m2) i.v. administration were determined in 20 patients with advanced malignancies undergoing peripheral blood hematopoietic progenitor-cell transplantation. Melphalan was assayed in plasma by a specific HPLC method with UV detection. Plasma levels of melphalan declined in a biexponential fashion with a mean terminal half-life of 83 minutes (range 52-168 minutes). Estimated peak plasma concentrations ranged from 1.65 to 14.5 micrograms/ml. Plasma levels were lower than the limit of quantitation of the method used (20 ng/ml) 24 hours after drug administration. The average volume of distribution and total clearance were 317 ml/min/m2 (range 127-797 ml/min/m2) and 37.9 l/m2 (range 15.4-108 l/m2), respectively. These parameters are similar to those reported in the literature. A weak correlation was found between total clearance of melphalan and creatinine clearance (p < 0.05). No relationship between the pharmacokinetics of melphalan and myelosuppression and non-hematologic toxicities was recovered. This pharmacokinetic study indicates that on the assumption that there is no more circulating melphalan after seven elimination half-lives, it may be possible to reinfuse autologous PBPC 10-20 hours after melphalan administration.

Adult↗
PubMedDate not supplied

Rapid development of drug resistance in human ovarian tumor xenografts after a single treatment with melphalan in Vivo.

Human ovarian tumors from A2780 cells were grown as xenografts in immunodeficient mice, treated with a single i.p. dose of melphalan and tumor cells were removed and placed into tissue culture. The cells from the treated tumors exhibited an approximately 2-fold resistance to melphalan in vitro compared to cells taken from untreated tumors. This degree of resistance was similar to that of cells from tumors formed from melphalan-resistant A2780-ME cells. The cells from the treated tumors were also resistant to cisplatin but not to doxorubicin. They contained approximately 2-fold higher levels of glutathione than cells from the untreated tumors. Exposure of the cells to buthionine sulfoximine (a specific inhibitor of glutathione biosynthesis) eliminated the difference in glutathione levels as well as the difference in sensitivity to melphalan. When tumor-bearing animals were treated with buthionine sulfoximine in addition to melphalan the resulting tumor cells were not resistant to the drug. Resistance could also be demonstrated in the tumors themselves in vivo: the growth of previously untreated tumors was severely inhibited by a high dose of melphalan (11.7 mg/kg) administered i.p. to the animals, whereas the growth of tumors which had received prior treatment with melphalan was unaffected by the subsequent high dose. The rapid development of drug-resistant tumor cells after a single drug treatment in vivo makes this an excellent system for the investigation of the mechanisms by which resistance develops as well as for use in the screening for agents which can prevent it.

Animals↗
PubMed1995

Reduction of tumour intracellular pH and enhancement of melphalan cytotoxicity by the ionophore Nigericin.

Nigericin is an ionophore which permits the influx of H+ ions into cells down a concentration gradient, thus reducing intracellular pH (pHi) when extracellular pH is low. The effects of nigericin on the pHi of solid murine tumours in vivo were examined using 31P magnetic resonance spectroscopy. Nigericin at 2.5 mg/kg i.p. reduced pHi by 0.2-0.3 pH unit in the KHT and RIF-I tumours but had no effect on pHi in the SCCVII/Ha tumour. In vitro studies have shown that reduced pH can increase the toxicity of melphalan. Therefore, the anti-tumour effect of combining nigericin with melphalan was also examined. Nigericin at 2.5 mg/kg i.p. given before various doses of melphalan resulted in substantial delay in growth of the RIF-I tumour over that induced by melphalan alone. This observation was confirmed by an in vivo/in vitro excision assay, where nigericin given before melphalan produced a 30-fold increase in cell killing. By contrast, no enhancement of melphalan-induced cell killing by nigericin was observed in the KHT and SCCVII/Ha tumours, using growth delay and in vivo/in vitro excision assays, respectively.

Animals↗
PubMed1980

Comparative pharmacokinetics of chlorambucil and melphalan in man.

We have studied the pharmacokinetics of orally administered chlorambucil and melphalan in patients with hematologic malignancies and solid tumors. With a standard oral dose of 0.6 mg/kg, chlorambucil showed much more rapid systemic appearance than did melphalan and had a mean peak plasma concentration and area under the plasma disappearance curve which was 3-4 times greater than that observed in patients receiving melphalan. Melphalan had extremely variable systemic availability which was not observed with chlorambucil, and was not related to problems in tablet formulation. Chlorambucil undergoes extensive active metabolism to phenylacetic acid mustard, whereas melphalan undergoes rapid chemical degradation and has little, if any, active metabolism. On a pharmacokinetic basis, chlorambucil's greater in vitro stability, its more rapid and predictable systemic availability after oral dosing, and its extremely low urinary excretion make it a more predictable alkylating agent for clinical use than melphalan, especially for patients with reduced renal function.

Biotransformation↗
PubMed1983

Pharmacokinetics of melphalan in children following high-dose intravenous injection.

The pharmacokinetics of high-dose IV melphalan (140 or 220 mg m-2) were studied after 12 administrations in 10 children (aged 2.5-16 years) undergoing chemotherapy for either neuroblastoma or Ewing's tumour. To assess whether a simpler and less expensive nitrobenzylpyridine (NBP) spectrophotometric assay for alkylating activity was a satisfactory alternative to high-pressure liquid chromatography (HPLC), the plasma melphalan concentration was estimated by both methods in five cases. Analysis of the disposition of melphalan gave a mean half-life of 1.3 +/- 1.0 (SD) h, clearance 18.4 +/- 9.4 l X h-1 X m-2, and apparent volume of distribution 26.3 +/- 18.0 l X m-2. These pharmacokinetic parameters were similar to those found in adults: no correlation was found between any parameter and age or glomerular filtration rate. NBP alkylating activity determinations yielded consistent results and good correlation with plasma melphalan concentration. However, concordance analysis indicated a consistent bias, the NBP assay always giving lower estimates of plasma melphalan concentration: HPLC assay therefore remains the method of choice for determining plasma melphalan pharmacokinetics.

Adolescent↗
PubMed1986

In vitro comparative studies of the myelotoxicity and antitumor activity of 6-[bis-(2-chloroethyl)-amino]-6-deoxy-D-glucose versus melphalan utilizing the CFU-C and HTSCA assays.

6-[Bis-(2-chloroethyl)-amino]-6-deoxy-D-glucose (C-6) is a new glucose-containing nitrogen mustard that has significant activity for murine P388 leukemia with relative sparing of bone marrow in mice. The in vitro myelotoxicity of C-6 compared with that of melphalan, a clinically active, myelosuppressive nitrogen mustard, was determined in the CFU-C assay in human bone marrow samples obtained from normal volunteers. There was no significant difference between the myelosuppressive actions of C-6 and melphalan at any of the concentrations used except for 4.0 microM, at which C-6 was significantly (P less than 0.05) more toxic than melphalan. Both agents decreased the number of bone marrow cell colonies to approximately 12% of control at 6.6 microM (1 h incubation), which is a good approximation of melphalan's CxT (concentration by time) in man. We used the human tumor stem cell assay (HTSCA) to investigate in vitro antitumor activity. We obtained two specimens of malignant melanoma and two of malignant ovarian carcinoma from patients not previously treated with chemotherapy. The antitumor activity of melphalan was either similar to or greater than that of C-6 at all concentrations utilized against any of the four tumor specimens, except at 1.3 microM for tumor I. In particular, there was no significant difference in the antitumor activities of the two agents at 6.6 microM. These results suggest that C-6 will not be less myelosuppressive than melphalan at doses that produce equivalent antitumor activity in man. In addition, C-6 did not demonstrate increased myelotoxicity for normal human bone marrow cells incubated in glucose-deficient medium as against medium containing 300 mg% glucose at any of the concentrations used. This suggests that C-6 is not transported into normal human bone marrow cells via the glucose transport system, despite the presence of a glucose moiety within the molecule.

Analysis of Variance↗
PubMed1988

Comparative brain and plasma pharmacokinetics and anticancer activities of chlorambucil and melphalan in the rat.

Equimolar doses of chlorambucil and melphalan (both 10 mg/kg) were administered i.v. to anesthetized rats, and the plasma and brain concentrations of chlorambucil, its metabolites 3,4-dehydrochlorambucil and phenylacetic mustard, and melphalan were determined by high-performance liquid chromatography from 5 to 240 min thereafter. Chlorambucil demonstrated a monophasic disappearance from plasma, with a half-life of 26 min. The compound was 99.6% plasma-protein-bound. Chlorambucil underwent beta-oxidation to yield detectable concentrations of 3,4-dehydrochlorambucil and substantial amounts of phenylacetic mustard in the plasma. Low concentrations of chlorambucil and phenylacetic mustard were detected in the brain. Calculated from the areas under the concentration-time curves, the brain:plasma concentration integral ratios of chlorambucil and phenylacetic mustard were 0.021 and 0.013, respectively. Melphalan demonstrated a biphasic disappearance from plasma, with half-lives of 1.9 and 78 min. The compound was approximately 86% plasma protein-bound. Low concentrations of melphalan were detected in the brain, and its brain:plasma ratio was 0.13. These data demonstrate that following the administration of chlorambucil and melphalan, only low concentrations of active drug are able to enter the brain. As a consequence, concentrations of both drugs that cause the complete inhibition of extracerebrally located tumor have no effect on those located within the brain. Further, the brain uptake of melphalan, although low, is greater than that of chlorambucil and its active metabolites, which coincides with its slightly greater intracerebral activity following the systemic administration of very high doses.

Amino Acids↗
PubMed1991

Kinetics of melphalan leakage during hyperthermic isolation perfusion in melanoma of the limb.

The kinetics of melphalan leakage into the peripheral blood were studied in 21 patients undergoing hyperthermic isolation perfusion of the upper or lower limb as an adjuvant treatment in high-risk melanoma; in 5 patients cisplatin was added. The melphalan concentrations in the peripheral blood rose predominantly during the first 20 min of perfusion and levelled out to an apparent steady state of about 0.28 micrograms/ml in upper extremity perfusions, and 0.34 (without cisplatin) and 0.37 micrograms/ml (with cisplatin) in lower extremity perfusion. Erythrocytes labelled with technetium Tc 99m, which were added concomitantly with melphalan to the perfusion medium, appeared in the systemic circulation of the patients at an almost constant rate of 0.32% (lower and upper limb perfusions without cisplatin and 0.37% (with cisplatin) of total tracer/min. This perfusate flow rate indicated by labelled erythrocytes completely explained the leakage of melphalan from the perfusion circuit into the peripheral blood. Peak concentrations of melphalan in the peripheral blood were observed immediately after reconstitution of normal hemodynamic conditions once isolation perfusion had been terminated. This fraction of melphalan might originate from tissue-binding sites, but also from vascular compartments; therefore, a thorough washing-out procedure might minimize this effect.

Adult↗
PubMed1995

Low-dose-melphalan-induced up-regulation of type-1 cytokine expression in the s.c. tumor nodule of MOPC-315 tumor bearers and the role of interferon gamma in the therapeutic outcome.

We have previously shown the importance of endogenous tumor necrosis factor (TNF) production for the curative effectiveness of low-dose melphalan (L-phenylalanine mustard) for mice bearing a large MOPC-315 tumor. In the current study we demonstrate that low-dose melphalan is actually associated with enhanced expression of mRNA for TNF alpha in the s.c. tumor nodule. Moreover, the expression of mRNA for interferon gamma (IFN gamma) and interleukin-12 (IL-12; p40) is also elevated at the tumor site. However, while elevation in the expression of mRNA for TNF alpha and IFN gamma is evident within 24 h after the chemotherapy, elevation in the expression of mRNA for IL-12(p40) is first evident 72 h after the chemotherapy. Moreover, neutralizing anti-IFN gamma mAb, like neutralizing anti-TNF mAb but not neutralizing anti-IL-12 mAb, reduced the curative effectiveness of low-dose melphalan for MOPC-315 tumor bearers. Studies into the mechanism through which IFN gamma mediates its antitumor effect in low-dose-melphalan-treated MOPC-315 tumor-bearing mice revealed that MOPC-315 tumor cells, which are not sensitive to the direct antitumor effects of TNF, display some sensitivity to the antiproliferative activity of high concentrations of IFN gamma. However, unlike TNF alpha, IFN gamma is unable to promote the generation of anti-MOPC-315 cytotoxic T lymphocyte activity and, in fact, exerts an inhibitory activity on CTL generation. Taken together, our studies illustrate that low-dose melphalan therapy of MOPC-315 tumor bearers is associated with the rapid elevation in the expression of mRNA for IFN gamma and TNF, two cytokines which are important for the curative effectiveness of low-dose melphalan, and which mediate their antitumor effect, in part, through distinct mechanisms.

Animals↗
PubMed2006

Decreased response rates by the combination of histamine and IL-2 in melphalan-based isolated limb perfusion.

Histamine (Hi) combined to melphalan in a rat experimental model of isolated limb perfusion (ILP) for lower limb soft tissue sarcoma, resulted in overall response rates (OR) of 66%. Likewise, ILP with interleukin-2 (IL-2) resulted in OR of 67%, when combined to melphalan, in the same experimental model. In systemic immunotherapy, the combination of IL-2 and Hi has been used for solid tumor treatment based on immunomodulatory effects. In this study, we used our well-established ILP experimental model to evaluate whether the synergistic effect between the two drugs seen in the systemic setting, could further improve response rates in a loco-regional setting. Histological evaluation was done directly and 24 h after ILP. Melphalan uptake by tumor and muscle were measured. Hi and IL-2 together, combined to melphalan in the ILP led to OR of only 28%. Histology of tumors demonstrated partial loss of Hi-induced hemorrhagic effect when IL-2 was present. Melphalan accumulation in the tumor when both Hi and IL-2 were added (3.1-fold) was very similar to accumulation with Hi only (2.8-fold), or IL-2 only (3.5-fold) combined to melphalan. In vitro there was no synergy between the drugs. In conclusion there was a negative synergistic effect between IL-2 and Hi in the regional setting.

Animals↗
PubMed2006

Pharmacokinetic and phase II study of heated intraoperative intraperitoneal melphalan.

BACKGROUND: Peritoneal surface malignancy resulting from local dissemination is a common manifestation of treatment failure of gastrointestinal cancers. Although the management of carcinomatosis has been improved with an aggressive surgical approach of extensive cytoreduction followed by heated intraoperative intraperitoneal chemotherapy, no patients are cured when there is residual disease after surgery. Melphalan (L-phenylalanine mustard) is a well-known antineoplastic alkylating agent which has markedly increased pharmacological activity with heat. The use of heated intraoperative intraperitoneal melphalan may provide a pharmacokinetic and clinical advantage in this group of gastrointestinal cancer patients who cannot be made cancer-free with cytoreductive surgery. METHODS: Thirteen patients with residual disease following cytoreductive surgery for peritoneal carcinomatosis were included in this study. After surgical resection and prior to anastomotic reconstruction, patients received intraperitoneal melphalan (70 mg/m2) in 3 l of 1.5% dextrose peritoneal dialysis solution at 41-42 degrees C for 90 min. Concentrations of melphalan were assessed in the peritoneal fluid, blood, urine and tumor nodules using high-performance liquid chromatography. RESULTS: During the 90 min of treatment 87.2 +/- 4.3% of the drug was absorbed from the perfusate/peritoneal fluid and 11.9 +/- 2.1% was excreted in the urine. The area-under-the-curve ratio of peritoneal fluid to plasma was 33.3 +/- 11.8 with an average peak plasma concentration of 0.82 +/- 0.24 microg/ml occurring at 28.5 +/- 13.1 min. Concentrations of melphalan in tumor nodules on the peritoneal surface were approximately ten times higher than in plasma with an average peak concentration of 7.2 +/- 4.2 microg/gm. The grade III/IV morbidity was 38%; there was no mortality. CONCLUSION: Approximately 90% of the drug was absorbed during the 90-minute procedure with a 30 times greater exposure of drug at the peritoneal surfaces than in the blood. Concentrations of the drug in peritoneal surface tumor nodules were approximately ten times greater than concentrations in the blood. These data demonstrate that heated intraoperative intraperitoneal melphalan could have a significant impact on the treatment of peritoneal surface malignancies.

Adult↗
PubMed1997

L-amino acid oxidase (LOX) modulation of melphalan activity against intracranial glioma.

These studies evaluated the efficacy of sequential pretreatment with L-amino acid oxidase (LOX) and LOX antiserum in the modulation of melphalan activity against intracranial glioma in athymic nude mice. LOX produced statistically significant (P < 0.01) depletion of the large neutral amino acids isoleucine, leucine, methionine, phenylalanine, tyrosine, and valine in murine plasma at doses of 100 and 200 micrograms administered intravenously. Polyclonal anti-LOX antibody was successfully produced in mice, rabbits, and goats subsequent to immunization with LOX. Staphylococcal protein A-purified rabbit anti-LOX serum inhibited approximately 50% of LOX activity in vitro relative to control samples. This antiserum was used in vivo to inactivate LOX after it had depleted the large neutral amino acids, thereby preventing LOX-mediated catabolism of melphalan. Inoculation of three mice with rabbit anti-LOX serum after the treatment with LOX (100 micrograms) reduced LOX activity by 100%, 89%, and 100% at 6 h compared with reductions of 80%, 59%, and 52% over the same period in animals receiving LOX alone. In three separate studies using groups of eight to ten mice bearing intracranial human glioma xenografts, pretreatment with LOX followed by anti-LOX serum increased the antitumor activity of melphalan as compared with treatments with melphalan plus LOX, melphalan plus anti-LOX serum, or melphalan alone.

Amino Acid Oxidoreductases↗
PubMed1998

The antiproliferative action of a melphalan hexapeptide with collagenase-cleavable site.

PURPOSE: The objective of the present study was to examine the relevance of collagenase in the antitumor action of a melphalan peptide (MHP) with a collagenase-cleavable sequence. The question was addressed as to whether collagenase may act as an activator or a target in the antiproliferative mechanism of MHP. METHODS: Melphalan was inserted into peptides representing the sequence Pro-Gln-Gly-Ile-Ala.Gly of the collagenase-cleavable site in collagens. Changes in growth and collagenase IV activities of HT-1080, HT-29, HT-168, and MCF-7 cell cultures were investigated. RESULTS: The present investigations provide data indicating that Pro-Gln-Gly-Ile-Mel-Gly (melphalan hexapeptide, MHP) is a substrate for both bacterial and 72-kDa type IV collagenases and that in this way it can generate Ile-Mel-Gly (melphalan tripeptide, MTP) of higher cytotoxic potency. Indeed, the formation of MTP was detected in the conditioned medium of HT-1080, a collagenase IV-producing human fibrosarcoma. In a comparison of equimolar concentrations of melphalan and its two peptide derivatives (MHP and MTP), superior antiproliferative action of MTP was seen in HT-29, HT-1080, and HT-168 tumor cell cultures. However, the relatively modest cytostatic actions of MHP were increased when bacterial collagenase was added to the cell cultures. After melphalan treatment, reduced levels of both 92 and 72-kDa type IV collagenases were seen in the HT-1080 cell cultures. However, the reduction of collagenase activity and the cell counts did not run parallel in the MTP- or MHP-treated cultures; indeed, collagenase activity related to cell numbers showed an elevated level. CONCLUSIONS: As the conversion of MHP to the more toxic MTP was detected in the presence of collagenases, it is possible that collagenase-directed activation of prodrugs may be a promising approach for the development of more selective cytostatic drugs against malignant tumors with high collagenase activities.

Antineoplastic Agents, Alkylating↗
PubMed1980

Reversible melphalan-induced lung damage.

Pulmonary toxicity occurs after the administration of several different chemotherapeutic agents. Pulmonary toxicity due to melphalan alone has not been documented. In the patient we describe respiratory symptoms and pulmonary infiltrates developed twice within two weeks of the second course of a monthly melphalan and prednisone regimen. Open lung biopsy revealed interstitial pneumonitis. The infiltrates cleared on both occasions when melphalan was withheld. Special studies performed seven weeks after the last dose of melphalan had been given revealed that the patient's alveolar macrophages suppressed phytohemagglutinin induced blastogenesis of his peripheral lymphocytes. Melphalan itself did not stimulate the blastogenesis of the peripheral lymphocytes. Melphalan should be added to the list of therapeutic agents that induce pulmonary disease. However, the pathogenesis of the disease remains to be elucidated.

Aged↗
PubMed1982

The effect of alkylating agents and other drugs on the accumulation of melphalan by murine L1210 leukaemia cells in vitro.

The effect of cytotoxic and other drugs on the accumulation of melphalan by L1210 murine leukaemia cells was studied. We have confirmed that uptake is an active process competitively inhibited by L-leucine. In 36 experiments in amino acid-free medium the mean concentration of melphalan taken up was 225 pmoles/10(6) cells. High pressure liquid chromatographic analysis showed that the majority of the drug is present as free native melphalan. 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) was the only drug that stimulated accumulation, but without significant effect on influx or efflux rates. Busulphan, chlorambucil, cyclophosphamide, interferon, methotrexate and prednisolone had no effect on accumulation after 30 min melphalan transport. Adriamycin, CCNU, methyl CCNU, mustine and vincristine all impaired melphalan accumulation as did the non-cytotoxic drugs aminophylline, chlorpromazine and ouabain. Adriamycin, aminophylline, chloropromazine, indomethacin and ouabain all reduced melphalan influx.

Alkylating Agents↗
PubMed1989

Glutathione and glutathione S-transferases in a human plasma cell line resistant to melphalan.

We report the development of a melphalan-resistant HS-Sultan human plasma cell line. The melphalan-resistant [MEL(R)] cell line was 16.7-fold more resistant to melphalan in vitro than the parent cell line [MEL(S)]. The wild type and MEL(R) HS-Sultan cell lines formed localized plasmacytomas when injected into nude mice. A dose-response effect of melphalan against the drug-sensitive plasmacytomas was present in vivo. A dose of 10 mg/kg of melphalan, which caused a 90% regression of MEL(S) plasmacytomas, had no effect on the MEL(R) plasmacytomas in vivo. In contrast to previous reports, there was no increase in the levels of glutathione (GSH) in the MEL(S) and MEL(R) plasmacytomas, suggesting that the association of elevated glutathione levels and melphalan resistance may not be common to all drug-resistant lines. In the MEL(R) plasmacytomas, there was a 1.5-fold induction of a pi type glutathione S-transferase (GST) as evidenced by isoelectric focusing (IEF) and Western blotting. This GST isoenzyme was purified and, although immunochemically similar to the pi type isoenzymes induced in other drug-resistant cell lines, was noted to have different functional characteristics. These data suggest that, depending on cell type and the drug studied, functionally different GST isoenzymes may be induced and they could be of importance in the development of drug resistance.

Animals↗
PubMed1987

The effect of hyperthermia on the cytotoxicity of melphalan in Chinese hamster ovary cells.

The heat stability of melphalan during incubation at temperatures from 37 degrees C to 45 degrees C was determined by spectrophotometric and HPLC analyses and by direct measurement of melphalan cytotoxicity using a colonogenic assay Although OD 250 changed little during exposure to temperatures up to 45 degrees C for periods of up to 1 h, the melphalan HPLC peak decreased as function of incubation time and temperature. Loss of cytotoxicity following heating paralleled the decay of the melphalan HPLC peak. Despite the inactivation of melphalan by heat, the cytotoxic effects of melphalan were enhanced at elevated temperatures from 38 degrees C to 42 degrees C and synergism was observed at lethal temperatures above 42 degrees C.

Animals↗
PubMed2006

Novel amidine analogue of melphalan as a specific multifunctional inhibitor of growth and metabolism of human breast cancer cells.

A novel amidine analogue of melphalan (AB4) was compared to its parent drug, melphalan in respect to cytotoxicity, DNA and collagen biosynthesis in MDA-MB-231 and MCF-7 human breast cancer cells. It was found that AB4 was more active inhibitor of DNA and collagen synthesis as well more cytotoxic agent than melphalan. The topoisomerase I/II inhibition assay indicated that AB4 is a potent catalytic inhibitor of topoisomerase II. Data from the ethidium displacement assay showed that AB4 intercalated into the minor-groove at AT sequences of DNA. The greater potency of AB4 to suppress collagen synthesis was found to be accompanied by a stronger inhibition of prolidase activity and expression compared to melphalan. The phenomenon was related to the inhibition of beta(1)-integrin and IGF-I receptor mediated signaling caused by AB4. The expression of beta(1)-integrin receptor, as well as Sos-1 and phosphorylated MAPK, ERK(1) and ERK(2) but not FAK, Shc, and Grb-2 was significantly decreased in cells incubated for 24h with 20 microM AB4 compared to the control, not treated cells, whereas in the same conditions melphalan did not evoke any changes in expression of all these signaling proteins, as shown by Western immunoblot analysis. These results indicate the amidine analogue of melphalan, AB4 represent multifunctional inhibitor of breast cancer cells growth and metabolism.

Amidines↗