Two Weeks Tomorrow…

This time two weeks ago I was getting ready to drive to Rennes the following day to pick up the wife. Approximately two weeks before that she had her high dose chemotherapy. The idea of this is to whack the fast growing cells with Melphalan and to take the patient pretty close to death’s door. Then by administering hematopoietic stem cells bring the patient back to life. While monitoring them very carefully under sterile conditions.

This from Wikipedia in italics.

 Melphalan belongs to the class of nitrogen mustard alkylating agents. It works by interfering with the creation of DNA and RNA.

                4-[bis(2-Chloroethyl)amino]-L-phenylalanine

                (2S)-2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanoic acid

Nitrogen mustards are cytotoxic organic compounds with the chloroethylamine (Cl(CH2)2NR2) functional group. Although originally produced as chemical warfare agents, they were the first chemotherapeutic agents for treatment of cancer. Nitrogen mustards are nonspecific DNA alkylating agents.

During World War II nitrogen mustards were studied at the Yale School of Medicine by Alfred Gilman and Louis Goodman, and classified human clinical trials of nitrogen mustards for the treatment of lymphoma started in December 1942. Also during World War II, an incident during the air raid on Bari, Italy, led to the release of mustard gas that affected several hundred soldiers and civilians. Medical examination of the survivors showed a decreased number of lymphocytes. After World War II was over, the Bari incident and the Yale group’s studies eventually converged prompting a search for other similar compounds. Due to its use in previous studies, the nitrogen mustard known as “HN2” became the first chemotherapy drug mustine.

Nitrogen mustards are not related to the mustard plant or its pungent essence, allyl isothiocyanate; the name comes from the pungent smell of chemical weapons preparations.

Nitrogen mustards (NMs) form cyclic aminium ions (aziridinium rings) by intramolecular displacement of the chloride by the amine nitrogen. This aziridinium group then alkylates DNA once it is attacked by the N-7 nucleophilic center on the guanine base. A second attack after the displacement of the second chlorine forms the second alkylation step that results in the formation of interstrand cross-links (ICLs) as it was shown in the early 1960s. At that time it was proposed that the ICLs were formed between N-7 atom of guanine residue in a 5’-d(GC) sequence. Later it was clearly demonstrated that NMs form a 1,3 ICL in the 5’-d(GNC) sequence.

Nitrogen mustards are powerful and persistent blister agents. HN1, HN2, HN3 are therefore classified as Schedule 1 substances within the Chemical Weapons Convention. Production and use is therefore strongly restricted.

So, there is an element of serendipity to the discovery of a chemotherapy drug.

Phenylalanine (symbol Phe or F)is an essential α-amino acid with the formula C9H11NO2. It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino acid is classified as neutral, and nonpolar because of the inert and hydrophobic nature of the benzyl side chain. The L-isomer is used to biochemically form proteins coded for by DNA. Phenylalanine is a precursor for tyrosine, the monoamine neurotransmitters dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and the skin pigment melanin. It is encoded by the codons UUU and UUC.

Phenylalanine is found naturally in the breast milk of mammals. It is used in the manufacture of food and drink products and sold as a nutritional supplement for its analgesic and antidepressant effects. It is a direct precursor to the neuromodulator phenethylamine, a commonly used dietary supplement. As an essential amino acid, phenylalanine is not synthesized de novo in humans and other animals, who must ingest phenylalanine or phenylalanine-containing proteins.

So, they gave her a form of phenylalanine with a nasty group attached which is soluble at physiological pH. This places the alkylating HN2 function right at the heart of the DNA biochemistry.

They put her through the wringer, she was very ill and only now is she able to do things like cook a baked potato which tires her out.

She came home two weeks ago tomorrow. The couch is getting a lot of use for napping, and I have discovered that the perfect temperature for milk when making hot chocolate is 93˚C. Above this is sticks to the sospan on the induction hob.

{For many years I thought that this was the correct spelling of saucepan in English. I even had arguments about it.}

There is a lull for recovery before the next two cycles of chemotherapy begin. Most of the summer we will back and forth to the hospital and Dexy’s Midnight Runners {dexamethasone not Dexedrine} will be playing once a week. These ‘roids do not assist sleeping!!

“Dextroamphetamine (D-AMP) is a central nervous system (CNS) stimulant and an amphetamine enantiomer that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant.”

I have to decide whether to try to get an appointment with the doctor about my post Covid bronchitis…Maybe I should wait and then when she is on the Dexy’s I can be on high dose Prednisolone.  Nah, not a good idea two people on ‘roids at the same time.

Anyway, the hedge is now 2/3 done, the trailer is full. My shoulders and back are tired and throbbing a little from the effort.  We have a treat. We can drive up to the tip and I can unload the trailer.

A day out that is not hospital themed.

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