Cytotoxic Chemotherapy and Cancer Development

Cytotoxic Chemotherapy Overview

• Cytotoxic chemotherapy treats cancers using varying drug regimens
• It inhibits cell proliferation through non-targeted mechanisms
• It relies on the fact that cancer cells proliferate faster than normal cells
• This information is divided into four segments, each approximately 10 minutes long
• It begins with an introduction, then covers drugs that inhibit cell division, damage DNA, or inhibit DNA synthesis

Cancer Development Stages

• Cancer development occurs in three stages
• Normal cells transform to produce dysregulated growth
• Cells proliferate to form tumors
• Tumor cells may then metastasize, seeding other organs via vascular and lymphatic systems
• Cells can dedifferentiate, becoming different from the original tumor and more resistant to drug therapy

Early Cancer Chemotherapy Discoveries

• Folic acid rich foods worsen childhood leukaemia
• Sidney Farber (Harvard Paediatric Pathologist) discovered that antagonism of folic acid might depress bone marrow shutting down excessive white cell production in leukemia
• Methotrexate was first used to treat in 1950
• Mustard nerve gases from WWI produce bone marrow depression
• Louis Goodman used mustard nerve gases to treat lymphosarcoma in 1942
• Cyclophosphamide was the first drug effective for solid tumours in 1959

Log Kill Model

• Cytotoxic cancer chemotherapy destroys a consistent fraction of cells with each dose
• Intermittent dosing reduces adverse effects, but allows cancer cell regrowth and resistance
• Chemotherapy aims for total cell kill, the immune system is less effective at clearing cancer cells
• Solid and disseminated tumour therapy aims to reduce tumour burden to zero
• One gram (10^9) of cells, the smallest detectable tumors, are when symptoms become apparent
• Therapy is intermittent, given in cycles ~21 days apart, to allow immune system recovery
• Adjuvant chemotherapy occurs after solid tumour surgery/radiation, treating micrometastases
• Neoadjuvant chemotherapy occurs before surgery
• Combination therapy uses drugs with different mechanisms and adverse effects

Cytotoxic Chemotherapy Effects

• It has an antiproliferative effect caused by driving cells to apoptosis, where cancer cells are more susceptible
• Non-solid tumors are more accessible to drug therapy
• Differentiated cells are less susceptible to drug therapy
• Cytotoxic chemotherapy does affect cellular invasiveness, tendency to metastasize or de-differentiation

Cancer Drug Combinations: Advantages

• Combination drug chemotherapy is more effective versus single-drug treatment for most cancers
• It allows maximal cell killing inside toxicity limits
• It's effective against broader range of cells
• It can delay the development of resistant cell lines

R-CHOP Example

• One example of the use of drug combinations in cancer chemotherapy is the non-Hodgkin lymphoma treatment
• In non-Hodgkin lymphoma, abnormal lymphocytes in bone marrow proliferate in lymph nodes, cause swelling, may metastasize
• Non-Hodgkin lymphoma forms ~4% of cancers in UK
• Hodgkin's is rarer, has different lymphocytes, giant binucleate Reed-Sternberg cells, easier to treat, 90% survival in 5 years
• Non-Hodgkin lymphoma symptoms consist of: swollen lymph nodes (neck, armpit, groin), abdominal/chest pain, fever and night sweats
• Common cancer drug combinations have acronyms based on used agents
• "R-CHOP" components: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisolone
• Cyclophosphamide alkylates DNA, Vincristine inhibits Mitosis, Doxorubicin induces DNA breaks, Prednisolone is a corticosteroid.
• Rituximab targets CD20, an important B-lymphocyte cell membrane protein

Cell Cycle and Drug Targets

• Cell proliferation is a major drug target
• Many cancer cells are arrested in G0, for example, solid tumours
• In the cell cycle duplicating the cellular content is in G1, and duplicating chromosomes is in S phase
• The G2 phase cell checks and repairs errors in chromosomal duplication
• Mitotic M phase cell separates into 2 daughter cells
• Cell cycle non-specific antiproliferative drugs: Ability to inhibit G0 cells, they are more effective against solid and slow growing tumors
• Examples include: Cyclophosphamide and platinum compounds
• Cell cycle-specific antiproliferative drugs examples: Glucocorticoids (G1), antimetabolites (S), topoisomerase inhibitors in S/G2, microtubular inhibitors in M phase

Combination Drug Administration

• Agents with the same toxicities must be combined at low doses of each drug
• Combine cytotoxic agents with different toxicities and MOA at full doses
• Cytoprotectant drugs minimize adverse effects, ex: folinic acid with methotrexate

Chemotherapy Adverse Effects

• Drugs target Cell Division, affecting all rapidly dividing tissues
• Drug action in S phase damages DNA and initiates apoptosis
• Rapid cell destruction with purine/urate precipitation can cause kidney damage
• Adverse effects include: bone marrow toxicity, hair loss and GI tract epithelium damage
• Other side effects: impaired wound healing, repressed growth, sterility and teratogenicity
• It can cause severe nausea and vomiting

Cell Growth and Division Inhibitors

• Drugs are split into 3 groups
• (1) Inhibitors of cell division like the vinca alkaloids
• (2) Inducers of DNA damage like the alkylating agents
• (3) Inhibitors of DNA synthesis like methotrexate

Vinca Alkaloids and Prednisolone as Cell Division Inhibitors

• There are two major inhibitors of the cell, including: vinca alkaloids and the taxanes
• This recording covers vincristine, used in R-CHOP for non-Hodgkin lymphoma where the 'O' in the acronym stands
• A second drug used in R-CHOP, prednisolone, is now thought to inhibit G1 phase of the cell cycle

Cell Division Inhibitors: Mitotic Spindles

• Mitotic spindles are structures formed from protein tubulin that affect cells in the cell division
• Chromosomes form chromatids in prophase, linked to mitotic spindles in metaphase that align, then separate in anaphase
• Spindle contraction produces daughter cells in telophase

Vinca Alkaloid Drug Target: Beta Tubulin

• Mitotic spindles are from tubulin protein
• Alpha tubulin (yellow) and beta tubulin (blue) make up tubulin heterodimers, assembled at the tubule's positive end and disassembled at the negative end
• The target protein for vinca alkaloids and taxanes is beta tubulin
• Vinca alkaloids bind selectively to beta tubulin, preventing tubulin polymerization
• Taxanes bind to differing beta tubulin sites on the tubule to prevent disassembly, stabilizing tubulin units
• Both drugs inhibit chromatid separation in metaphase, preventing cell division

Vinca Alkaloids: Therapeutic Use

• Vinca alkaloids treat cancers like leukemia, lymphoma, and bladder cancer
• MOA: Inhibition of cell division
• Route: Intravenous Infusion
• Pharmacokinetics: Liver metabolism excretion
• Major dose limiting effects:
  • Vinblastine causes myelosuppression
  • Vincristine is neurotoxic

Taxanes Bind Beta Tubulin

• The taxanes bind to beta tubulin on the inside of the microtubule, prevent microtubule depolymerization
• The stabilizing effect straightens mitotic spindles, unable to function which inhibits cells during metaphase

Taxanes: Therapeutic Use

• The taxanes are therapeutic for metastatic ovarian, breast, lung, GI and genitourinary cancer, and for head and neck cancer
• Mechanism of action is the inhibition of cell division
• It's delivered by route IV infusion
• Liver metabolizes The taxanes (CYP2C8)
• Paclitaxel causes hypersensitivity, neutropenia, and myalgia
• Docetaxel causes less hypersensitivity, more neutropenia, and less neurotoxicity
• Other effects include fluid retention and leg edema

Review of Microtubular Inhibitors

• Microtubular inhibitors = Vinca alkaloids + taxanes, affecting the M-Phase
• There is also Glucocorticoids = Prednisolone which affects the phase G1

Prednisolone MOA

• Oral glucocorticoid prednisolone affects G1 of the cell cycle and reduces lymphocyte entry into mitosis during cell division
• It inhibits CDK 2 by dephosphorylating retinoblastoma protein (Rb1), inhibiting E2F and cyclin E/A
• This steroid drug reduces hypersensitivity responses
• Prednisolone can inhibit nausea and vomiting

Review of Three Phases of Inhibitors

• M-phase inhibitors consist of Vincristine, Vinblastine and Paclitaxel+ Docetaxel
• G1-Phase inhibitors consist of Prednisolone and Palbociclib

Cytotoxic Chemotherapy Induces DNA Damage and Inhibits DNA Synthesis

• This section covers the mechanisms for drugs that cause direct DNA damage, inhibits cell proliferation through apoptosis
• This is for the following agents: Alkylating agents, Platinum compounds, and Topoisomerase inhibitors

DNA Damage caused by Different Methods

• (1) Inhibit DNA helix separation, Cyclophosphamide/Platinum
• (2) Induce DNA strand breaks via Bleomycin
• (3) Prevents DNA supercoiling, ie Etoposide
• Doxorubicin works by multiple MOA

Inihibition of DNA Helix

• Alkylating Agents must have bifunctional molecules to interact with two guanine bases
• The drugs include Cyclophosphamide + Nitrosoureas+ Carbazines + Platinum
• Cyclophosphamide is an anticancer drugs
• Helices cannot be separated and become easily to strand breaks

Cyclophosphamide

• Cyclophosphamide is a prodrug activated in liver for subsequent DNA interactions
• It is metabolizes into phosphoramide mustard & acrolein
• Phosphoramide mustard has covalent links between guanine bases
• DNA code can misread, strand can break
• Non-cell cycle specific is its MOA where It inhibits both diving and rest cells by inhibiting DNA to cells at rest
• It majorly doses which limits hemorrhagic nephritis

Additional Alkylating Agents

• Other bi functional agent in cyclophosphamide
• Chorambucil has similar and same busalfan links to guanine with both being non-cell cycle spefic
• Nitrosoureas treat brain tumors because they are lipid-soluble

Platinum Compounds Affect DNA

• Platinum is capable of cross-linking DNA which inhibits mitosis and DNA
• They are delivered in IV or Peritoneal manner
• Platinum causes a lot of advances but can major dose limiting side effects: aggressive hydration requirements, long time severe vomiting, hearing loss and sensation

Bleomycin Induces DNA Strand Breaks

• Bleomycin achieves by generating superoxide radicals, affecting during Cell Cycle
• Major dose adverse is Pulmonary fibrosis with toxicity
• There is no effect over Myleosuppresion

Topoisomerase Drug

• DNA has strands and helices which needs untwising
• During enzyme topoisomersae II, drug binds at one and cleavage begins that is released from segment

More on Etoposide

• Is a glycoside of podophyllotoxin, extracted from a US plant
• Approved 1983 to target tumours in the lung
• It needs Enzyme to be able prevent DNA strands from apoptosis but can cause hair loss, and leukaemia

Anthracyclines: Doxorubicin

• Anithracycniles is the drug and is derived from 1960's soil
• Major cause effect is heart issues causing free radicals
• Has a radio mimic ability that can be avoided with weekly intake and in liposome

All MOA of DNA Induction

• MOA involve inhibiting separation and inducing separation into DNA causing strand breakage

Inhibitors of Cell Division

• For DNA and Cell, there are methods to inhibit by inducing anti tumor and alkylating

Targeting DNA Synthesis

• The following targets the metabolism of DNA involved and is a good use

Folate Antagonists

• It is a good method
• Methotrexate acts by inhibiting cells from inhibiting the metabolism
• The methotrexate allows a good and helpful means to perform with all others

Review of the Various Inhibitors

• Capecitabine contains 5-FU and has majorly works to inhibit cell
• 5- FU reduces production and decreases damage

Cytarabine

• Inhibits cytidine from helping with lymphoma
• Good for both maintenance and suppression of what has occurred from the damages

Mercaptopurine

• Blocks the creation of more tumor by reducing all components together in the purine
• A purine in general serves to help suppress the functions it must deal with in particular ways

Adenosine

• Creates fludarabine into terminators and helps to avoid damages from recurring

Summary of the Most Common Drugs

• The most important of these drugs will help understand the process of tumors and inhibitors

Drug Action Summary with Hodgkins and Non Hodgkins

• R-CHOP is to cover all that it offers of hodgkin and Non Hodgkins
• Specific functions of what is happening allows a way to understand better

Patient information of R-CHOP

• Frequency and good and bad of patients to be able to avoid issues over time

Tumours and Lysis

• Tumour lysis is what helps and can allow the kidney to have less problems in the blood and body

Hair Loss

• A good cold cap will induce constriction but comes at a high price point to maintain

Vomiting

• Vomiting results from anti prolific which will be what helps in the body

Treatment from Vomiting

• Lowering women's intake who may not require it as much will ensure less to get in the system

Side-effects for drugs in chemotherapy

• Drugs needs full functions to ensure what they are used for are better in the long run with a combination of drugs

Adverse Effects in Specific Locations

• This is in R CHOP where it can lead to nerves with some with others that are negative

Cyclophosphamide

• This helps the ureter but causes renal issues, this can lower by fluids

Vincristine and Periphery Issues

• Causes all sense organs and some in the mind to be unhinged in ways, though time does heal them

Doxorubicin

• A low and high that causes issues over time. To reduce this, time and attention are given into doses

Chemo Man

• Chemo has great ability to do all good as much as bad in the human body. It important to look at and be aware