Biochemical

A compound that can target cells expressing the estrogen receptor (ER), and produce predominantly 3-MeA adducts in those cells has been designed and synthesized. This compound produces mainly the 3-MeA adduct upon reaction with calf thymus DNA, and binds to the ER with a relative binding affinity of 51% (estradiol = 100%). The compound is toxic to ER-expressing MCF-7 breast cancer cells, and pre-treatment with the ER antagonist fulvestrant abrogates the toxicity. Pre-treatment of MCF-7 cells with netropsin, which inhibits N3-adenine methylation by the compound, resulted in a threefold decrease in the toxicity. These results demonstrate the feasibility of this strategy for producing 3-MeA adducts in targeted cells [1].

Absorption, Distribution and Excretion
In rats, approximately 30% of the radioactivity injected as (14)CH3 methyl methanesulfonate was exhaled as (14)CO2 within 30 hr, and an additional 20% was recovered from urine. In mice given a single ip dose ... approximately 34% ... was recovered from urine and 27% as (14)CO2.
In mice and rats methyl methanesulfonate is rapidly distributed throughout the body, including the CNS. In pregnant rats (21st day of gestation), transplacental passage into fetuses occurred within 2 min after iv injection. Following iv injection of 100 mg/kg body weight to rats, no detectable amount of methyl methanesulfonate were found in blood serum after 2 hr.
... If administered intraperitoneally, it reaches the excretion mechanism readily in activated form.

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Metabolism / Metabolites
Various urinary metabolites (methylmercapturic acid sulfoxide, 2-hydroxy-3-methylsulfinylpropionic acid, methylsulfinylacetic acid and a mixture of methylmercapturic acid and N-(methylthioacetyl)glycine) were identified in rats after iv administration of (14)CH3-methyl methansulfonate during the first 16 hr. About 80% of the excreted radioactivity was accounted for by these metabolites, resulting from an initial methylation of cysteine residues by methyl methanesulfonate.

Interactions
The combined effects of methyl methanesulfonate and ethyl methanesulfonate on the induction of 6-thioguanine resistant mutants and chromosome aberrations were examined in Chinese hamster V79 cells. Cells were simultaneously treated with ethylmethanesulfonate at a concentration of D20 /SRP: D20 = concentration required to reduce cell survival to 20%/ and methyl methanesulfonate at various concentrations for 3, 6 or 9 hr. In other experiments cells were simultaneously treated with methyl methanesulfonate at a concentration of D20 and ethyl methanesulfonate at various concentrations for 3, 6 or 9 hr. The mathematical analysis of the combined effects of both chemicals for cell killing (cytotoxicity) and 6-thioguanine resistant mutations indicates that synergistic interactions were observed for both cell killing and mutations induced by methyl methanesulfonate and ethyl methanesulfonate. The frequency of chromosome aberrations induced by simultaneous treatment with methyl methanesulfonate at a concentration of D20 and ethyl methanesulfonate at various concentrations for 3 hr was additive. However, the frequency of chromosome aberrations induced by ethyl methanesulfonate at a concentration of D20 and methyl methanesulfonate at various concentrations for 3 hr was not significantly different from those induced by methyl methanesulfonate alone.
Ethanol itself did not induce any apparent chromosome aberrations in Chinese hamster ovary cells. However, post-treatment with ethanol potentiated the chromosome aberrations induced by ... methyl methanesulfonate. ... Chromatid exchanges were predominantly increased in cultures treated with ... methyl methanesulfonate ... and then with ethanol. ... Post-treatment with acetaldehyde, the major metabolite of ethanol, also potentiated the chromosome aberrations induced by ... methyl methanesulfonate. ... The main types of aberrations potentiated by posttreatment with acetaldehyde were similar to those by posttreatment with ethanol. /Methyl methanesulfonate/

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Non-Human Toxicity Values
LD50 Rat oral 225 mg/kg
LD50 Rat ip 140 mg/kg
LD50 Rat sc 125 mg/kg
LD50 Rat iv 175 mg/kg

[1]. Bioorg Med Chem. 2011 Sep 1;19(17):5093-102.

Methyl Methanesulfonate can cause cancer according to an independent committee of scientific and health experts.
Methyl methanesulfonate is a colorless to amber liquid. (NTP, 1992)
Methyl methanesulfonate is a methanesulfonate ester resulting from the formal condensation of methanesulfonic acid with methanol. It has a role as an alkylating agent, a genotoxin, a carcinogenic agent, a mutagen and an apoptosis inducer.
Methyl Methanesulfonate is a stable, colorless, combustible liquid that emits toxic fumes of sulfoxide when heated to decomposition. Methyl methanesulfonate is used for laboratory purposes as a catalyst in chemical synthesis and has been tested clinically as a cancer chemotherapeutic agent. This substance is an alkylating agent and acts as a mutagen by altering and damaging DNA and is reasonably anticipated to be a human carcinogen. (NCI05)
An alkylating agent in cancer therapy that may also act as a mutagen by interfering with and causing damage to DNA.

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Mechanism of Action
Monofunctional, methylating agents, such as methyl methanesulfonate, produce primarily 7-methyl-guanine, an adduct that is believed to be innocuous due to its inability to block nucleic acid synthesis or cause misincorporation of bases in newly synthesized DNA. This altered base, however, has been postulated to be indirectly deleterious to cells due to the increased lability of the /glycosyl/ bond, leading to the formation of noninstructive apurinic sites in the DNA template. Another abundant lesion formed is 3-methyladenine. This product has been shown to block nucleic acid synthesis, but direct evidence that it is a lethal moiety in mammalian cells is lacking. The primary promutagenic lesions formed by methylating agents are O6-methylguanine and O-4-methylthymine, both of which can cause base transitions in newly synthesized DNA. O-Methylguanine is formed to a higher extent than O-4-methylthymine, and it has been demonstrated that guanines preceded at 5' by adenine are twice as likely to be methylated at the O6 position as those preceded by thymine, indicating the existence of base sequence effects on adduct formation. Another lesion formed by methylating agents is the methylphosphotriester. This persistent adduct clearly slows nucleic acid synthesis in cell-free systems, but its effect on gene expression or mutagenesis in cells is not clear. ... Longer chain alkylating agents produce similar spectra of damage, but the relative proportions of the adducts formed are significantly different. The lesions formed in the greatest quantities are the alkylphosphotriesters, which represent more than 50% of the total damage to the DNA. The promutagenic lesion that becomes increasingly important with these agents is O4-alkylthymine. It is produced in amounts five- to tenfold greater than occur with methylating agents, and, although it is slowly removed from DNA, its half-life is significantly longer than that for O6-alkylguanine, making it potentially more important in causing point mutations following DNA synthesis.

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Drug Warnings
Therapeutic application of total doses of between 2.8-800 mg/kg bw over period of up to 350 days to 13 cancer patients led to significant GI and hepatic toxic effects.

C2H6O3S

110.13

110.003

66-27-3

Methyl methanesulfonate-d3;91419-94-2

4156

Colorless to light yellow liquid

1.2±0.1 g/cm3

202.1±9.0 °C at 760 mmHg

20ºC

104.4±0.0 °C

0.4±0.4 mmHg at 25°C

1.406

-0.57

0

3

1

6

105

0

S(C([H])([H])[H])(=O)(=O)OC([H])([H])[H]

MBABOKRGFJTBAE-UHFFFAOYSA-N

InChI=1S/C2H6O3S/c1-5-6(2,3)4/h1-2H3

methyl methanesulfonate

METHYL METHANESULFONATE; 66-27-3; Methyl mesylate; Methanesulfonic acid methyl ester; Methylmethanesulfonate; methylmethane sulfonate; Methanesulfonic acid, methyl ester; Methyl methanesulphonate;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 100 mg/mL (908.02 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (22.70 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (22.70 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (22.70 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)