In this article, we will discuss chemotherapy agents that target a specific phase in the cell-cycle process to inhibit cancer cell proliferation.
Traditional Chemotherapy
Cell-cycle-specific agents belong to a larger group of chemotherapy agents known as traditional chemotherapy. They are referred to as traditional because they do not target specific cancer-related proteins or genes, and they may target all cells (both cancerous and healthy). Due to this, dosing is done by body-surface-area-based dosing (BSA). A wrong dose or route can be lethal for these agents.
Traditional chemotherapy agents can have significant effects on bone marrow, kidney function, and liver function. As such, labs to monitor these functions should be monitored regularly. Use the acronym PAST when thinking about what labs to obtain for these agents: P-Platelet, A-ANC, S-Serum creatinine, and T-Total bilirubin.
The most common side effects across the board are myelosuppression, mucositis, diarrhea, cancer-induced nausea/vomiting, and hair loss (alopecia).
There are two main types of traditional chemotherapy based on the mechanism of cell killing: Cell-cycle specific (time-dependent) and cell-cycle non-specific (dose-dependent).
In this discussion, we will go over cell-cycle specific.
Quick Review of the Cell Cycle
The cycle begins with the G1 phase, which stands for growth phase 1. In this phase, the cell grows and makes proteins required for DNA replication to prepare itself for the S phase.
The second phase is the S phase or the DNA synthesis phase. This is where DNA replication happens to generate another copy of the DNA for the daughter cell.
The third phase is the G2 phase, which stands for growth phase 2. In this phase, the cell will prepare itself for cell division by making the necessary proteins and preparation.
The four and last phase of the cell cycle is the M phase or the mitosis phase. This is where cell division occurs to generate a daughter cell.
Cell-cycle-specific agents target one of these phases. All of them with the intention to halt the uncontrolled cell proliferation seen in cancerous cells. Keep in mind that most of these agents are non-specific to just cancer cells but also target normal cells that rapidly proliferate as well, such as hair and gut cells, leading to adverse effects.
Most of the cell-cycle-specific agents target either the S phase or the M phase.
S Phase (DNA Synthesis)
Remember that the S phase is where DNA synthesis occurs. Agents that target this phase work to stop DNA synthesis either by stopping the replication itself or stopping the initiation of DNA synthesis.
There are two main groups: Antimetabolites and topoisomerase inhibitors
Antimetabolites
Antimetabolites interfere with DNA synthesis. There are three subgroups: folate antagonists, purine analogs, and pyrimidine analogs. A quick reminder that purine bases are adenine and guanine, and pyrimidine bases are thymine, cytosine, and uracil.
Folate Antagonists
Folate is important in nucleic acid production, as we discussed in the previous discussion about anemia. Folate antagonists work by blocking dihydrofolate reductase (DHFR), an enzyme that converts folate to tetrahydrofolate, leading to an inhibition of RNA and DNA synthesis.
There are two agents: Methotrexate and Pemetrexed. Both of these agents inhibit DHFR. The primary difference is that pemetrexed also inhibits TS and GARFT as well.
Due to the degree of inhibition, both of these agents require rescue agents.
- Methotrexate: leucovorin (AKA folinic acid – a reduced form of folic acid)
- Pemetrexed: folic acid (QD) and vitamin B-12 (Q 3 weeks)
Pemetrexed is very hard on the kidney and is contraindicated in low kidney function (CrCl <45 mL/min). Because of this, NSAIDs should be avoided for 5 days prior to the dose and 2 days after.
In the hospital, patients who are on methotrexate should have their plasma MTX level measured 24 hours after the MTX dose. Depending on the level, the dose of leucovorin is adjusted accordingly. This level of precaution is warranted because MTX can distribute into the third space. This means in patients with edema or ascites, MTX can stay inside the body longer, leading to more exposure, more toxicity, and adverse reactions. These patients need more time on leucovorin.
Methotrexate is yellow, just like folic acid. There are a lot of drug-drug interactions.
- Highly protein bound
- P-gp substrate
- Renal excretion
- Acidified urine increases serum MTX (increased reabsorption leading to crystallization and kidney damage)
- PPI (inhibit elimination)
Dose-limiting toxicity: myelosuppression (without leucovorin)
Pyrimidine Analogs
There are a lot of pyrimidine analogs. The cytidine analog agents that we will discuss are azacitidine, cytarabine, and gemcitabine. The thymidine analog agents that we will discuss are capecitabine and fluorouracil.
Azacitidine (PO) – the hypomethylation agent. They interfere with DNA methyltransferase.
- Used in mild leukemia and myosarcoma (hematologic malignancies)
- Allow for normal transcription to happen to allow cells to function normally and will eventually die off (double negative)
- ADR: myelosuppression and mild GI toxicity
Cytarabine (IV, SQ, IT, liposomal) – Similar structural as cytidine with an altered C2 from OH to H. This change in the base stops base pairing, causing the termination of replication.
- Once it gets inside the body, cytarabine gets converted to the triphosphate form and is incorporated into DNA.
- ADR: Neurologic toxicity (at high dose – head-writing test with each dose to assess) and conjunctivitis (dexamethasone eye drop should be used with and up to2 days post-dose).
- Dose-limiting toxicity: myelosuppression
Gemcitabine (IV) – the deoxycytidine. Same scenario as cytarabine where C2 is altered. C2 is altered to 2 Fs in the alpha and beta positions.
- Once it gets inside the body, gemcitabine gets converted to the triphosphate form and is incorporated into DNA.
- ADR: Flu-like syndrome (develops immediately after administration – last less than 48 hours)
- Dose-limiting toxicity: myelosuppression (consider if flu-like syndrome last beyond 48 hours)
Fluorouracil – Dual mechanism. First, the inhibition of thymidylate synthase results in an inhibition of thymidine formation. Fluorouracil is converted to 5-dUMP, which does the inhibition. Second, the incorporation into RNA and inhibiting synthesis.
- Toxicities are based on the timing of administration.
- Bolus dose is known to cause more myelosuppression.
- The continuous dose is known to cause more hand-foot syndrome, mucositis, and diarrhea (usually with the oral formulation)
- Must be adjusted for renal dysfunction
- Leucovorin can be given with fluorouracil to enhance the effect of fluorouracil by allowing fluorouracil to bind to thymidylate synthase with higher affinity than without leucovorin. The dose of leucovorin depends on institutions.
Capecitabine – Prodrug of fluorouracil
Purine Analogs
Both of the agents we will discuss today are guanine analogs: fludarabine and mercaptopurine. They are converted by hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) to triphosphate form and incorporated into DNA.
Fludarabine – the C2 is altered.
Mercaptopurine – Switched to SH from O and eliminated the ammonia group from guanine.
- Inactivated by xanthine oxidase (allopurinol and febuxostat – inhibit this). If taken together, there is more risk of toxicity with mercaptopurine. The mercaptopurine dose should be lowered by 75% if taken together.
Both fludarabine and mercaptopurine can cause myelosuppression and immunosuppression. This means that the patient cannot make more and cannot use the current supply of immune cells either. This leads to an increased risk of opportunistic infections, especially rare ones, such as PCP pneumonia. Patients should be put on a prophylaxis antibiotic regimen throughout the therapy and for several months after. Bactrim is the most common agent for this.
Thiopurine methyltransferase (TPMT) can inhibit both of these agents. There is a common allele mutation that leads to inactive or deficiency in the activity, leading to excessive myelosuppression and more toxicity. A genetic testing should be done prior to the initiation and dose reduction as needed.
Topoisomerase Inhibitors
Topoisomerase is an enzyme that is responsible for the unwinding of DNA strands. There are two main types of topoisomerase: topoisomerase I and topoisomerase II. Topoisomerase I performs single-strand DNA breaks. Topoisomerase II performs double-strand DNA breaks.
There are two subgroups of topoisomerase inhibitors that are chemotherapy agents: Camptothecins and Epipodophyllotoxins. Camptothecins are derived from the Chinese camptotheca acuminate plants. Epipodophyllotoxins are derived from the May apple plants.
Camptothecins – “Significant diarrhea”
Camptothecins work through the inhibition of topoisomerase I. This means that the DNA strand cannot be resealed when it breaks to unwind.
There are two camptothecins that we will discuss today: Topotecan and Irinotecan.
Topotecan – This was the first agent that is not so popular anymore due to severe hepatotoxicity. It also causes myelosuppression.
Irinotecan – this medication is also known as CPT-11. Its structure is very similar to neostigmine and has similar effects, leading to excess acetylcholine and acute cholinergic storm.
- Some adverse reactions from this storm include acute and violent diarrhea and increase secretion throughout the body (tearing, sweating).
- Atropine should be used as pre-medication for the cholinergic storm.
- Irinotecan has another active metabolite known as SN38. This metabolite causes significant GI irritants through the glucuronidation pathway. One of the mutations, UGT1A1 polymorphism, causes a dysfunction in this glucuronidation pathway, leading to increased toxicity and prolonged exposure to SN38.
Epipodophyllotoxins – “Severe hepatotoxicity”
Epipodophylltoxins work through the inhibition of topoisomerase II. There is only one agent in this class that we will discuss: Etoposide.
Teniposide is rarely used due to severe hepatotoxicity risk. It is available as IV and PO. There is an IV to PO conversion. PO dosing is 2x of IV dosings.
- Teniposide must be refrigerated (PO).
- Poor solubility can lead to an infusion reaction. This is why it is typically solubilized with alcohol 30%. If this solution is infused too fast, it can cause extreme hypotension. Usually, the minimum infusion time is 30 minutes, typically an hour.
- Teniposide can also cause precipitation and leaching of DHEP from PVC bags. A dose greater than 0.4 is especially at risk. Typically, we deal with this by increasing the amount of fluid in the IV bag.
M Phase (Mitosis)
This a quick reminder that mitosis is where cell division happens. An important component of this process is microtubules. Microtubules need to be able to separate in order to generate daughter cells successfully. If this is inhibited, then cell division fails, and the cell cannot proliferate further.
This is the theory behind the agents that target the M phase. There are 4 main subgroups of agents that target the M phase: Taxanes (pacific yew tree bark), Epothilone (bacteria), Vinca alkaloids (periwinkle plants), and Eribulin (sea sponge).
Taxanes – “total body hair loss”
Taxanes stabilize microtubules to make microtubules less likely to separate and prevent depolymerization. If this cannot happen, chromosomes and cells cannot separate, leading to apoptosis.
ADRs: Infusion reaction (thick substance – poorly soluble), peripheral neuropathy (primarily sensory – tingling and burning), alopecia (total body hair loss), peripheral edema (more common with docetaxel – give dexamethasone), and myelosuppression.
Two primary agents are Paclitaxel and Docetaxel.
Paclitaxel – mixed with cremophor (castor oil), which is associated with infusion reaction. Patients should be pre-medicated with diphenhydramine, famotidine, and dexamethasone.
Docetaxel – mixed with Tween 80 (surfactant). There is less risk of reaction, but we still should pre-medicate the same way.
Nab-Paclitaxel – binding with albumin. This greatly reduces the infusion reaction risk. They don’t need pre-medication generally. Because we are using albumin, we have to be mindful of religious preference and protein tracking.
Epothilones – “LR or buffered NS”
There is only one agent in this subgroup: ixabepilone. This agent work to stabilize microtubule, similarly to taxanes. It was derived from bacteria.
Pre-medications are required: diphenhydramine and famotidine, but no dexamethasone.
ADRs are similar to taxanes. Just like taxanes, it is poorly soluble and needs to be in LR or buffered NS.
Vinca Alkaloids – “Do Not Give Intrathecal”
Vinca alkaloids are derived from the periwinkle plant. They bind to tubulin subunits of microtubules preventing polymerization, which means that microtubules cannot form.
ADRs: Peripheral neuropathy (autonomic leading to severe constipation), tissue damage (if vesicant gets out of bloodstream – dose-dependent), Hyponatremia (SIADH), NO myelosuppression.
Do NOT give intrathecally – guarantee a slow and extremely painful death. It is impossible to reverse. NEVER dispense the vinca alkoloids in a syringe.
The most common agent is vincristine (Oncovin). Other agents are vinblastine and vinorelbine.
Eribulin – “Sea sponge”
Eribulin is very similar to vincristine and shares the same mechanism of action. The adverse effect profile is most like vinblastine with less neuropathy.