DT-Web

DB01042 - Melphalan


Identification
Name Melphalan
Accession Number DB01042 (APRD00118)
Type small molecule
Description An alkylating nitrogen mustard that is used as an antineoplastic in the form of the levo isomer - melphalan, the racemic mixture - merphalan, and the dextro isomer - medphalan; toxic to bone marrow, but little vesicant action; potential carcinogen. [PubChem]
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 305.2
Groups approved
Monoisotopic Weight 304.074533244
Pharmacology
Indication For the palliative treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. Has also been used alone or as part of various chemotherapeutic regimens as an adjunct to surgery in the treatment of breast cancer, alone or in combination regimens for palliative treatment of locally recurrent or unresectable in-transit metastatic melanoma of the extremities, as well as for the treatment of amyloidosis with prednisone.
Mechanism of action Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases (primarily at the N-7 position of guanine and to a lesser extent, at the N-3 position of adenine), forming monoadducts and resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations.
Absorption Incomplete, variable, 25-89% post oral dose
Protein binding Moderate to high (60 to 90%), primarily to albumin and, to a lesser extent, alpha 1-acid glycoprotein. 30% is irreversibly bound.
Biotransformation Melphalan is not actively metabolised, it spontaneously degrades to mono and dihydroxy products.
Route of elimination The 24-hour urinary excretion of parent drug in these patients was 10% ? 4.5%, suggesting that renal clearance is not a major route of elimination of parent drug.
Toxicity Vomiting, ulceration of the mouth, diarrhea, and hemorrhage of the gastrointestinal tract; The principal toxic effect is bone marrow suppression. LD50=11.2 mg/kg (orally in rat)
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions
Drug Mechanism of interaction
Bendamustine Increases toxicity through pharmacodynamic synergism. Additive myelosuppression.
Cyclosporine Melphalan increases toxicity of cyclosporine
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Food Interactions
  • Take on an empty stomach. Food decreases bioavailabilty by approximately 30%. Increase liquid intake.

Targets


DNA
Name DNA
Gene Name Not Available
Pharmacological action yes
Actions cross-linking/alkylation
References
  • Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. - Pubmed
  • Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. - Pubmed
  • Monahan SD, Subbotin VM, Budker VG, Slattum PM, Neal ZC, Herweijer H, Wolff JA: Rapidly reversible hydrophobization: an approach to high first-pass drug extraction. Chem Biol. 2007 Sep;14(9):1065-77. - Pubmed
  • Lee PC, Kakadiya R, Su TL, Lee TC: Combination of bifunctional alkylating agent and arsenic trioxide synergistically suppresses the growth of drug-resistant tumor cells. Neoplasia. 2010 May;12(5):376-87. - Pubmed
  • Wang F, Li F, Ganguly M, Marky LA, Gold B, Egli M, Stone MP: A bridging water anchors the tethered 5-(3-aminopropyl)-2'-deoxyuridine amine in the DNA major groove proximate to the N+2 C.G base pair: implications for formation of interstrand 5'-GNC-3' cross-links by nitrogen mustards. Biochemistry. 2008 Jul 8;47(27):7147-57. Epub 2008 Jun 13. - Pubmed
  • Vasquez KM: Targeting and processing of site-specific DNA interstrand crosslinks. Environ Mol Mutagen. 2010 Mar 1. - Pubmed
  • Dimopoulos MA, Souliotis VL, Anagnostopoulos A, Bamia C, Pouli A, Baltadakis I, Terpos E, Kyrtopoulos SA, Sfikakis PP: Melphalan-induced DNA damage in vitro as a predictor for clinical outcome in multiple myeloma. Haematologica. 2007 Nov;92(11):1505-12. - Pubmed
  • Chen Q, Van der Sluis PC, Boulware D, Hazlehurst LA, Dalton WS: The FA/BRCA pathway is involved in melphalan-induced DNA interstrand cross-link repair and accounts for melphalan resistance in multiple myeloma cells. Blood. 2005 Jul 15;106(2):698-705. Epub 2005 Mar 31. - Pubmed
  • Souliotis VL, Dimopoulos MA, Episkopou HG, Kyrtopoulos SA, Sfikakis PP: Preferential in vivo DNA repair of melphalan-induced damage in human genes is greatly affected by the local chromatin structure. DNA Repair (Amst). 2006 Aug 13;5(8):972-85. Epub 2006 Jun 15. - Pubmed
  • Loeber R, Michaelson E, Fang Q, Campbell C, Pegg AE, Tretyakova N: Cross-linking of the DNA repair protein Omicron6-alkylguanine DNA alkyltransferase to DNA in the presence of antitumor nitrogen mustards. Chem Res Toxicol. 2008 Apr;21(4):787-95. Epub 2008 Feb 14. - Pubmed
DTHybrid score Not Available

Transporters


Solute carrier family 22 member 3
Name Solute carrier family 22 member 3
Gene Name SLC22A3
Actions inhibitor
References
  • Shnitsar V, Eckardt R, Gupta S, Grottker J, Muller GA, Koepsell H, Burckhardt G, Hagos Y: Expression of human organic cation transporter 3 in kidney carcinoma cell lines increases chemosensitivity to melphalan, irinotecan, and vincristine. Cancer Res. 2009 Feb 15;69(4):1494-501. Epub 2009 Feb 3. - Pubmed
DTHybrid score 0.1818
Large neutral amino acids transporter small subunit 1
Name Large neutral amino acids transporter small subunit 1
Gene Name SLC7A5
Actions Not Available
References
  • Moscow JA, Swanson CA, Cowan KH: Decreased melphalan accumulation in a human breast cancer cell line selected for resistance to melphalan. Br J Cancer. 1993 Oct;68(4):732-7. - Pubmed
DTHybrid score 0.4311

Predictions


Id Partner name Gene Name Score
6151 Monocarboxylate transporter 10 SLC16A10 0.1081
866 Large neutral amino acids transporter small subunit 2 SLC7A8 0.0771
6556 Elongation factor Tu GTP-binding domain-containing protein 1 EFTUD1 0.0665
1566 Corticoliberin CRH 0.058
6145 Solute carrier family 22 member 1 SLC22A1 0.0493
6144 Solute carrier family 22 member 2 SLC22A2 0.0476
758 Thyroid hormone receptor alpha THRA 0.047
301 Kynurenine--oxoglutarate transaminase 1 CCBL1 0.043
346 Thyroid hormone receptor beta-1 THRB 0.0406
6153 Solute carrier organic anion transporter family member 4A1 SLCO4A1 0.0376
6150 Solute carrier organic anion transporter family member 4C1 SLCO4C1 0.0365
6158 Solute carrier organic anion transporter family member 1C1 SLCO1C1 0.0336
118 Organic cation/carnitine transporter 2 SLC22A5 0.0322
1490 Solute carrier organic anion transporter family member 1B1 SLCO1B1 0.0273
594 Thyroxine-binding globulin SERPINA7 0.0253
1588 Multidrug resistance protein 1 ABCB1 0.0249
833 Organic cation/carnitine transporter 1 SLC22A4 0.0243
4119 Cytochrome P450 2D6 CYP2D6 0.0234
563 Thyroid peroxidase TPO 0.0202
4512 Cytochrome P450 3A4 CYP3A4 0.0199
6142 Solute carrier family 22 member 8 SLC22A8 0.0197
378 Alpha-2C adrenergic receptor ADRA2C 0.0169
6157 Solute carrier organic anion transporter family member 1B3 SLCO1B3 0.0153
373 Transthyretin TTR 0.0148
6139 Solute carrier organic anion transporter family member 1A2 SLCO1A2 0.0141
587 Serum albumin ALB 0.014
3876 Aromatic-L-amino-acid decarboxylase DDC 0.0136
163 D(1B) dopamine receptor DRD5 0.0131
281 5'-AMP-activated protein kinase subunit beta-1 PRKAB1 0.0127
1732 ATP-binding cassette sub-family G member 2 ABCG2 0.0125
432 D(4) dopamine receptor DRD4 0.0124
6154 Multidrug and toxin extrusion protein 1 SLC47A1 0.0123
4924 Cytochrome P450 2C8 CYP2C8 0.0123
1636 Trace amine-associated receptor 1 TAAR1 0.0122
638 D(3) dopamine receptor DRD3 0.0121
629 Alpha-2B adrenergic receptor ADRA2B 0.0119
4200 Cytochrome P450 1A2 CYP1A2 0.0119
6141 Sodium/bile acid cotransporter SLC10A1 0.0116
862 Multidrug resistance-associated protein 1 ABCC1 0.0112
6024 Cytochrome P450 1A1 CYP1A1 0.0111
23 D(1A) dopamine receptor DRD1 0.0107
318 Alpha-2A adrenergic receptor ADRA2A 0.0106
5626 Nucleoside diphosphate kinase B NME2 0.0105
199 Monocarboxylate transporter 8 SLC16A2 0.0105
4757 Cytochrome P450 2C9 CYP2C9 0.0103
982 Cocaine- and amphetamine-regulated transcript protein CARTPT 0.0101
4118 Cytochrome P450 3A5 CYP3A5 0.01
831 D(2) dopamine receptor DRD2 0.01
131 Synaptic vesicular amine transporter SLC18A2 0.0098
713 Sodium-dependent dopamine transporter SLC6A3 0.0098
4097 Neuronal acetylcholine receptor subunit alpha-9 CHRNA9 0.0098
556 Alpha-1A adrenergic receptor ADRA1A 0.0098
6107 Cytochrome P450 3A7 CYP3A7 0.0094
342 P protein [Includes: DNA-directed DNA polymerase P 0.0091
612 P protein [Includes: DNA-directed DNA polymerase P 0.0091
1539 Oligopeptide transporter, small intestine isoform SLC15A1 0.0088
161 Tubulin beta chain TUBB 0.0085
312 Tubulin beta chain TUB2 0.0085
6030 Cytochrome P450 2B6 CYP2B6 0.0085
5294 Nucleoside diphosphate kinase A NME1 0.0084
6013 Cytochrome P450 2E1 CYP2E1 0.0084
6070 Nischarin NISCH 0.0083
6016 Cytochrome P450 2C19 CYP2C19 0.0082
1735 Canalicular multispecific organic anion transporter 1 ABCC2 0.008
6164 POU domain, class 5, transcription factor 1 POU5F1 0.0078
3941 Amine oxidase [flavin-containing] A MAOA 0.0077
5718 Cytochrome P450 2A6 CYP2A6 0.0077
2472 Voltage-gated potassium channel kcsA 0.0075
6366 Voltage-gated potassium channel kcsA 0.0075
540 Sodium-dependent noradrenaline transporter SLC6A2 0.0074
3923 Cholinesterase BCHE 0.0072
677 Choline-phosphate cytidylyltransferase A PCYT1A 0.007
766 Beta-2 adrenergic receptor ADRB2 0.0069
789 Alpha-1D adrenergic receptor ADRA1D 0.0068
3970 Voltage-dependent N-type calcium channel subunit alpha-1B CACNA1B 0.0067
2164 Multidrug resistance-associated protein 4 ABCC4 0.0067
1729 Solute carrier family 22 member 6 SLC22A6 0.0066
1898 Cytochrome P450 1B1 CYP1B1 0.0065
401 Glutamate [NMDA] receptor subunit zeta-1 GRIN1 0.0063
1064 DNA (cytosine-5)-methyltransferase 1 DNMT1 0.0063
3939 Amine oxidase [flavin-containing] B MAOB 0.0062
6138 Multidrug resistance protein 3 ABCB4 0.0061
5126 Arginase rocF 0.0061
709 ATP-sensitive inward rectifier potassium channel 1 KCNJ1 0.0061
776 Bile salt export pump ABCB11 0.0059
1341 Histamine H3 receptor HRH3 0.0057
124 Histamine H2 receptor HRH2 0.0057
164 Histamine H4 receptor HRH4 0.0054
1709 Canalicular multispecific organic anion transporter 2 ABCC3 0.0054
740 Argininosuccinate synthase ASS1 0.0054
865 Argininosuccinate synthase ASS1 0.0054
2680 Argininosuccinate synthase argG 0.0054
3194 Argininosuccinate synthase argG 0.0054
6136 Multidrug resistance-associated protein 5 ABCC5 0.0053
824 Sodium-dependent serotonin transporter SLC6A4 0.0053
1181 Alpha-1-acid glycoprotein 1 ORM1 0.0053
632 Alpha-1B adrenergic receptor ADRA1B 0.0049
492 Histamine H1 receptor HRH1 0.0049
6148 Multidrug resistance-associated protein 7 ABCC10 0.0048
624 Guanidinoacetate N-methyltransferase GAMT 0.0047
29 Tubulin beta-1 chain TUBB1 0.0046
220 Sodium channel protein type 5 subunit alpha SCN5A 0.0043
4203 Histamine N-methyltransferase HNMT 0.0043
6014 Cytochrome P450 2A13 CYP2A13 0.0042
514 Potassium voltage-gated channel subfamily H member 6 KCNH6 0.0042
772 Potassium voltage-gated channel subfamily H member 7 KCNH7 0.0042
2539 Tubulin alpha-1 chain TUBA4A 0.0042
147 Aldehyde dehydrogenase, mitochondrial ALDH2 0.0041
465 Calmodulin CALM1 0.0041
6432 Transporter snf 0.0039
102 DNA topoisomerase I, mitochondrial TOP1MT 0.0038
702 UMP-CMP kinase CMPK1 0.0034
6022 UDP-glucuronosyltransferase 1-1 UGT1A1 0.0034
193 Beta-1 adrenergic receptor ADRB1 0.0034
2300 Lysozyme E 0.0034
3633 Lysozyme R 0.0034
5597 Lysozyme 17 0.0034
3929 Phosphoethanolamine/phosphocholine phosphatase PHOSPHO1 0.0034
3927 Choline transporter-like protein 3 SLC44A3 0.0034
549 Choline-phosphate cytidylyltransferase B PCYT1B 0.0034
769 High-affinity choline transporter 1 SLC5A7 0.0034
264 Choline/ethanolamine kinase [Includes: Choline kinase beta CHKB 0.0034
3933 Choline/ethanolaminephosphotransferase CEPT1 0.0034
1686 Choline transporter-like protein 1 SLC44A1 0.0034
3926 Choline transporter-like protein 2 SLC44A2 0.0034
861 Choline kinase alpha CHKA 0.0034
700 Choline dehydrogenase, mitochondrial CHDH 0.0034
3925 Choline transporter-like protein 4 SLC44A4 0.0034
576 Choline O-acetyltransferase CHAT 0.0034
3922 Phospholipase D2 PLD2 0.0034
3924 Phospholipase D1 PLD1 0.0034
5682 Ribonuclease pancreatic RNASE1 0.0033
756 Sex hormone-binding globulin SHBG 0.0033
6163 Copper-transporting ATPase 2 ATP7B 0.0032
6165 Copper-transporting ATPase 1 ATP7A 0.0032
101 Potassium voltage-gated channel subfamily H member 2 KCNH2 0.0031
1353 DNA topoisomerase 1 TOP1 0.003
3552 DNA topoisomerase 1 topA 0.003
6146 High affinity copper uptake protein 1 SLC31A1 0.003
1517 Beta-3 adrenergic receptor ADRB3 0.003
153 Dopamine beta-hydroxylase DBH 0.003
4152 Superoxide dismutase [Cu-Zn] SOD1 0.0029
4773 Deoxycytidine kinase DCK 0.0029
908 Glutathione S-transferase theta-1 GSTT1 0.0029
828 Phenylalanine-4-hydroxylase PAH 0.0029
3109 Phenylalanine-4-hydroxylase phhA 0.0029
6143 Solute carrier family 22 member 7 SLC22A7 0.0028
6106 Cytochrome P450 2C18 CYP2C18 0.0028
274 Muscarinic acetylcholine receptor M5 CHRM5 0.0027
1360 Sphingomyelin phosphodiesterase SMPD1 0.0027
136 Estrogen receptor ESR1 0.0027
1024 Solute carrier family 22 member 11 SLC22A11 0.0027
450 Muscarinic acetylcholine receptor M4 CHRM4 0.0027
896 Glutathione S-transferase Mu 1 GSTM1 0.0025
2157 NAD(P)H dehydrogenase [quinone] 1 NQO1 0.0024
51 Muscarinic acetylcholine receptor M3 CHRM3 0.0024
4604 Liver carboxylesterase 1 CES1 0.0024
1757 Myeloperoxidase MPO 0.0023
617 Muscarinic acetylcholine receptor M2 CHRM2 0.0023
3810 Catechol O-methyltransferase COMT 0.0023
948 Neuronal acetylcholine receptor subunit beta-2 CHRNB2 0.0023
6080 Neuronal acetylcholine receptor subunit alpha-5 CHRNA5 0.0023
6082 Neuronal acetylcholine receptor subunit beta-3 CHRNB3 0.0023
6018 UDP-glucuronosyltransferase 1-9 UGT1A9 0.0023
502 5-hydroxytryptamine 2A receptor HTR2A 0.0023
6104 Dimethylaniline monooxygenase [N-oxide-forming] 1 FMO1 0.0023
904 Glutathione S-transferase P GSTP1 0.0023
380 Cytochrome P450 17A1 CYP17A1 0.0023
103 Muscarinic acetylcholine receptor M1 CHRM1 0.0022
6081 Neuronal acetylcholine receptor subunit alpha-6 CHRNA6 0.0021
6098 Potassium voltage-gated channel subfamily D member 2 KCND2 0.0021
6099 Potassium voltage-gated channel subfamily D member 3 KCND3 0.0021
737 Mineralocorticoid receptor NR3C2 0.0021
6078 Neuronal acetylcholine receptor subunit beta-4 CHRNB4 0.002
6101 Dimethylaniline monooxygenase [N-oxide-forming] 3 FMO3 0.0019
614 Progesterone receptor PGR 0.0019
6031 Cytochrome P450 3A43 CYP3A43 0.0018
805 Cytochrome P450 11B1, mitochondrial CYP11B1 0.0018
6079 Neuronal acetylcholine receptor subunit alpha-3 CHRNA3 0.0018
6085 Fatty acid-binding protein, intestinal FABP2 0.0018
458 Neuronal acetylcholine receptor subunit alpha-10 CHRNA10 0.0018
6017 Cholesterol side-chain cleavage enzyme, mitochondrial CYP11A1 0.0017
474 Acetylcholinesterase ACHE 0.0016
1284 Nuclear receptor subfamily 1 group I member 2 NR1I2 0.0016
3811 Cytochrome P450 19A1 CYP19A1 0.0014
813 Neuronal acetylcholine receptor subunit alpha-2 CHRNA2 0.0014
146 Androgen receptor AR 0.0014
947 Neuronal acetylcholine receptor subunit alpha-4 CHRNA4 0.0014
4095 Neuronal acetylcholine receptor subunit alpha-7 CHRNA7 0.0014
869 Estrogen receptor beta ESR2 0.0013
1632 Solute carrier organic anion transporter family member 2B1 SLCO2B1 0.0013
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