chemotherapy

Anti-cancer drugs - DNA targeting

Include alkylating agents, intercalating agents, and chain cutters.

Alkylating agents

  • Highly electrophilic species, looking for nucleophilic sites to attack, and forming covalent bonds to bases in DNA 
  • Prevent replication and transcription 
  • Toxic side effects (e.g. alkylation of proteins) 
  • Bind in the major groove of DNA
  • Both types cross-link DNA by covalently bonding to nitrogen of base pairs.
  • Binding of nucleic acid bases results in miscoding and distortion. 
  • Distortion of DNA prevents excision by HMG proteinspermanent damage. 
  • Transcription and replication prevented, tumour growth slows. 

Two electrophilic sites on an anticancer drug can cause interstrand and intrastrand cross-linking.

  • Preference for 1,2-GG or 1,2-GC linkage sites, with interstrand or intrastrand linkage, is dictated by drug chemical structure 
  • Other linkage adducts are possible. Eg 1,3-GCG, 1,2-GA. 
  • Monofunctional adducts are also possible 

Chlormethine (a nitrogen mustard)

  •  Chlormethine is highly reactive, toxic side effects. 
  • Lead compound for many less toxic mustard derivatives. 
  • Methyl (CH3 ) group has positive inductive effect – promotes loss of chloride – see mechanism 

Less toxic chlormethine analogues:

  • Melphalan:  e- withdrawing ring lowers Nu strength of N, less reactive drug, less side effects, less toxic. Mimics PhAla, carried into cells by transport proteins. 
  • Uracil mustard:  Uracil ring is e-withdrawing, less reactive alkylating agent. Mimics a nucleic acid base, concentrates in fast growing cells.
  • Cyclophosphamide:  Most commonly used alkylating agent, Non-toxic, orally active prodrug. Acrolein associated with toxicity.
  • Busulfan: Causes interstrand cross-linking. Sulphonate group withdraws electrons, adjacent carbon subject to Nu attack by DNA bases. 
  • Dacarbazine – A diazine:  Prodrug activated by oxidation in liver, decomposes to form methyldiazonium ion. Alkylates guanine groups 

INTERCALATING AGENTS

 Aminoacridines eg Proflavine

Antibiotics - Dactinomycin

  • Extra binding to sugar phosphate backbone by cyclic peptide 
  • Intercalates via minor groove of DNA double helix 
  • Prevents unwinding of DNA double helix 
  • Blocks transcription, blocks DNA-dependent RNA polymerase 

Anthracyclines eg Doxorubicin (adriamycin) 

  •  Extra binding to sugar phosphate backbone by NH3 Planar rings and Anthracyclines eg Doxorubicin (adriamycin) 
  • Intercalates via major groove of DNA double helix 
  •  A topoisomerase poison - blocks action of topoisomerase II by stabilising DNA-enzyme complex 

CHAIN CUTTERS 

Calicheamicin g1 I antitumour agent 

  •  Nucleophilic attack on trisulphide chain starts a rearrangement process. 
  • This interacts with DNA to generate a DNA diradical, which reacts with oxygen, resulting in chain cutting.

Bleomycins (BLM)

  • Highly active head, neck, testicular cancer (Hodgkin lymphoma) 
  • Single and double-strand cleavage of DNA with several reduced metal ions and O2 , Fe(II) highest in vivo activity. 
  • Three regions - 
  • bithiazole DNA binding domain (DBD) locks BLM into the minor groove, 
  • carbohydrate domain (CHD) H-bonds BLM to sugar phosphate of DNA 
  • metal binding domain (MBD) bonds to Fe(II)    

Mechanism

  • A reaction with hydrogen peroxide gives Fe(III) and hydroxyl radicals which abstract H atoms and cut the DNA chain. 
  • Fe2+ + H2O2 Fe3+ + OH. + OH− Fenton mechanism 

Lungs and skin have low levels of BLM hydrolase - higher sensitivity and toxicity. Pneumonitis occurs in about 10% of patients, progresses to pulmonary fibrosis. Over-expressed in malignant cells, resistance to bleomycin    

Summary of Anti-Tumour Specificity for DNA 

Major groove alkylators 

  • GG interstrand - N-mustards, nitrosoureas. 
  • GG intrastrand - methanesulphonates. 
  • GC-interstrand - nitrosoureas, triazines. 

Minor groove intercalators 

  • GG interstrand – anthracyclines. 
  • GC-interstrand – actinomycins, acridines. 

Minor groove chain cutters 

  • GC or GT intrastrand – bleomycins 
Control

There is nothing scarier than something that is out of your control..

Like cancer consuming someone you love so dearly and not being able to take the pain away..

It’s these types of situations that make you stop and realise how cruel life can be..

I’m so scared to lose you..

Whether that be soon or in years to come.. Just keep fighting and I will always be here to support you

3

Before shaved head, shaved head, 4 years to the day later 😊
4 years ago my hair felt like dried pine needles and if you touched it it fell out 😛 when I went to the wig store they were like “you gotta shave this today you won’t have anything left in a couple days” and so on the spot they pulled out the clippers and bzzzzzed it all off 😛

I never cried about my hair. Being bald was kinda on my bucket list, just minus the chemo part 😂

I’m so incredibly happy to have it back. And finally, for the first time, back to the length it was before any of that happened. Mentally the toughest part of chemo for me was living with the repercussions of it years after anyone could tell I’d been sick. It felt like going through puberty awkward stages for a second time, and I was already a late bloomer 🙄 It’s just hair, but it can be so hard to be sexy or feminine or pretty without it. Now I feel all of these things more than ever 😁

I love u hair please stay with me forever or at least for like 30 or 40 years yknow 😛

Smart Drug Targets the Deadliest Brain Cancer for Destruction

Physicians and researchers at Houston Methodist Hospital have designed a new drug to treat patients with GBM, the most aggressive, incurable brain cancer.

“Glioblastoma multiforme (GBM) is the most aggressive brain cancer with no cure. Chemotherapy resistance has limited the use of temozolamide, a drug used to prolong the life of these patients,” said Martyn Sharpe, Ph.D., associate research professor of neurosurgery at Houston Methodist Hospital and a senior investigator on the study. “In an animal model of human brain cancer, combining the smart drug with chemotherapy prolonged life by over six fold.”

In research findings presented at the Society for Neuro-Oncology annual conference, a team of researchers led by scientist Sharpe and neurosurgeon David S. Baskin, M.D. director of the Kenneth R. Peak Brain and Pituitary Tumor Center at Houston Methodist Hospital invented a targeted way to overcome chemotherapy drug resistance and destroy the deadliest brain tumors while sparing surrounding brain tissue.

Results from the study showed that the smart drug is nontoxic in normal cells but transformed in GBM cells into a compound that blocks chemotherapy resistance, allowing for the destruction of aggressive brain cancer cells.

GBM and other brain cancers express high levels of a protein termed Monoamine oxidase B or MAOB, which converts the inactive drug into a compound that prevents chemotherapy resistance.

These results support further testing of PAM-OBG as a potential drug candidate for the treatment of patients with GBM or other cancers with high MAOB protein levels.

huffingtonpost.com
Chemotherapy Isn't Only for Cancer Patients
Upon hearing the word 'chemotherapy,' most people jump to the same conclusions, with the same general consensus on how chemo works, who receives it and what side effects it has on the body. The truth is chemotherapy isn't only for cancer patients, and affects each patient differently depending on how it is used.

A great wee article. I have had to take chemotherapy drugs to treat my Crohn’s and so have many other Crohn’s warriors

Hello loves!
I’m still alive…though a lot has been happening lately.
⭐I have osteosarcoma.
⭐I’m taking chemo (just finished my 3rd cycle now)
⭐I’m bald
⭐I will have a foot amputation at the end of this month 😐
⭐I will f-ing get through this and nothing will stop me ☺

As a destresser I started doing a bit of silly doodles/comics about cancer and stuff and decided to post some here 😛 Hope you like them

In general, about 95% I meet/talk to are super supportive of the state I’m in and I’ve never seen so much kindness and selflessness as while I’m sick…but I do get the occasional “ wtf ” comment that pisses me off.
Anyways, here is one of them (I’ll try to post them regularly )
Love ya all!! ❤

Hey-oh! So…. Tomorrow I do my second round of chemo. I have no idea how it’s going to affect me this time around, but if I disappear for a while, that’s why. For my new followers, don’t worry, nothing terminal. I have an autoimmune disorder that is treated with chemo a few times a year, and I’m actually really excited because this is the one where we expect to see the most improvement in my condition. I will be back!

Actual statements made by physicians I've visited:

“I’m not sure what’s going on with you neurologically; I’m going to refer you to a Multiple Sclerosis specialist”. - Neurologist

“I believe you have CNS Lupus”. - (Second Opinion Neurologist and MS Specialist).

“You don’t seem to have Lupus but I’m going to treat you with a moderate dose of prednisone anyway and see if you respond positively”. - (Second Opinion) Rheumatologist

“You don’t seem to have Lupus but I’m going to treat you with a very low dose of chemotherapy and see what happens”. “Maybe your daily temperature of 100.6 is your new normal and you just have to get used to it”.- (Third Opinion) Rheumatologist; who btw, is a nationally known author of medical textbooks on the subject of SLE and often a featured specialist on many TV programs. He also happens to be a complete asshole.

“I see you take Cymbalta. Did you know that if you were to have more orgasms you probably wouldn’t need that medication.” Later on in visit: “We need to talk more about your sexual assault ”, *as he read my neuropsychiatric assessment and said with disgustingly perverted interest.*
- (Fourth opinion Rheumatologist who is also an author on books about Lupus. I came very close to reporting him for inappropriate conduct).

“Do not come see me or ask me about any symptoms related to your autoimmune diseases.” - Primary Care Physician

“You definitely have Systemic Lupus Erythematosus”. - (First Rheumatologist and last opinion sought at Dept of Rheumatology at John’s Hopkins University Hospital. He was by far, the best doc who treated me.)

“You present a very complex case and in the field of medicine that’s never a good thing”. - (Said in some way by ALL physicians who examined me). 😩

  • <p> <b>Methotrexate:</b> so you know that food you love???<p/><b>Me:</b> yeah?<p/><b>Methotrexate:</b> it's gonna taste like metal now, forever.<p/><b>Me:</b> but how? Why???<p/><b>Methotrexate:</b> DO NOT QUESTION OR I'LL TAKE ANOTHER<p/></p>
CANCER UPDATE

So I had a doctor’s appointment today, everything is as fine as it should be. Blood levels are normal, none of the tumors have been growing. I talked about my pains and the extreme fatigue I’ve been experiencing, it’s all normal and it can take up to 2 years to recover. Pains I likely gotta deal with the rest of my life but I deal.

Getting into a small surgery where they remove one tumor from my neck, it’s not a dangerous tumor but it might decrease my pain a bit in that area. It’s no biggie. Next check up will be around September-October. All and all I’m very relieved. Not only is everything under control I got answers as to why I have been still so ill. So I don’t feel so… lost anymore.

Here’s a baby hedgie not relevant to this topic at all but it’s very cute.

anonymous asked:

I'm curious to know your feels about GP vets administering chemotherapy to animals. I'm assuming tablet form is ok? But I'm not sure about IV forms. And just from personal experience I have found PPE protocols to be severely lacking when using chemo agents, is this something you've seen as well? Poor PPE is something that worries me a lot about our profession :/

While it’s certainly possible to handle chemotherapy badly, places I’ve worked have been very careful with it. Too many staff members concerned about their ovaries.

A vet clinic can actually purchase adequate Personal Protective Equipment, and acquire chemotherapy in pre-measured doses to minimize handling and risk of spillage. There are special intravenous sets you’re supposed to use, and particular disposal protocols for afterwards.

So you can set out to do it properly, the resources are available for us. I have a very healthy respect for chemotherapy agents, especially Doxorubicin which can dissolve through cotton pants if spilled.

The bigger difficulty from a technical point of view is having the right protocol, as cancer treatment advances all the time. Lymphoma is occasionally treated in the clinic, because it’s the most common type of cancer we encounter and get reasonably good results. For everything else, if the owner wants to pursue chemo, then I recommend at least one consult with a specialist who will confirm the protocol.

So it’s perfectly possible to do chemotherapy well and properly in general practice, it just takes effort.