In this article, we will discuss chemotherapy agents that exhibit effects on the cell-cycle process as well as other cellular effects to inhibit cancer cell proliferation.
Traditional Chemotherapy Agents
Cell-cycle non-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 non-specific.
Cell-Cycle Non-Specific Agents
These agents exert their effect throughout the cell cycle, not targeting any specific phase of the cell cycle. The cell kill is proportional to the dose. Like cell-cyle-specific agents, these agents target all cells, regardless of whether it is a normal cell or a cancerous cell. ALL agents are considered hazardous drugs and tend to have effects on fertility. Most agents also have adverse effects of acute toxicity.
The agents that we will go over in this article are 1) alkylating agents, 2) platinum agents (, 3) anthracyclines, and 4) anthracenedione.
Alkylating Agents
In general, alkylating agents are prodrugs that are transformed in the body into positive ions. These positive ions attach themselves to DNA strands and halt DNA synthesis by causing mispairing and strand breakage. The most common location for attachment is the N7 atom of guanine. There are three mechanisms by which these positive ions attach themselves: crosslinking, alkyl groups, and intercalation. In general, most alkylating agents can present acute toxicity.
There are many subgroups of alkylating agents: Nitrogen mustards, Alkyl sulfonates, Aziridines, Triazenes, and Nitrosoureas.
Nitrogen Mustards – “Pulmonary fibrosis”
Agents include cyclophosphamide and ifosfamide. These agents work to form a cross-linkage between DNA base pairs.
After a dose is given, we typically see a drop in neutropenia with 6-10 days nadir and thrombocytopenia with 10-14 nadir.
Long-term toxicity: pulmonary fibrosis, seizures, pulmonary edema, and secondary leukemias.
Cyclophosphamide and ifosfamide – additional toxicities from its metabolite, acrolein, which can cause damage to the bladder (hemorrhagic cystitis). This can be prevented by hydration and a dose in the morning so the patients have all day to urinate it out. Mesna can be used with ifosfamide to minimize toxicity. It binds to acrolein, preventing acrolein from binding to the bladder. Mesna should be dosed at least 60% of the acrolein dose, typically 1:1.
They also have another metabolite: chloracetaldehyde, which can cause kidney toxicity and neurotoxicity. Methylene blue can reverse the effect of this metabolite.
Ifosfamide generates more acrolein than cyclophosphamide, which is why cyclophosphamide is used more.
Alkyl Sulfonates – “Seizure prophylaxis”
There is only one alkyl sulfonate that we will discuss: Busulfan. It is commonly used in hematologic malignancies. At high doses, it can dose pulmonary toxicity, unusual skin pigmentation, and neurotoxicity.
This neurotoxicity can lead to seizure, as such, seizure prophylaxis, typically Keppra, is needed.
Aziridines – “Sweat”
Thiotepa and Altretamine are the two agents in this subgroup. The key characteristic of aziridine is that they secrete in sweat and can lead to skin breakdown.
Patients on thiotepa must have an intense skincare regimen, avoid tight clothing, and keep the room temperature cool to reduce the amount of sweat.
Triazenes – “Three”
Dacarbazine, Procarbazine, and Temozolomide are agents in this subgroup. Temozolomide is an oral equivalent of dacarbazine.
Dacarabazine – sensitivity to light, photodecomposition, injection site pain (given with lidocaine)
Procarbazine – MOAI inhibitor (avoid with tyramine-rich foods and other MAOIs – disulfiram-like reactions)
Temozolomide – Use in brain cancer in combination with radiation therapy. It is very immunosuppressive and requires PCP prophylaxis.
Nitrosureas – “Delayed myelosuppression”
Carmustine is an agent from this subgroup. This medication penetrates the blood-brain barrier very well and is used in brain metastasis. It can cause delayed myelosuppression with a nadir of 4-6 weeks (instead of 10 days). Carmustine also comes as wafers known as the Gliadel wafer, which is put directly into the site in the brain.
Platinum Agents – “Alkylating-like”
This subgroup includes cisplatin, carboplatin, and oxaliplatin. All of them contain platinum moiety. Just as seen in piercing, platinum can have a delayed skin reaction that is not seen until 6-8 cycles into the treatment. They work on creating cross-linkage between intrastrand DNA.
Cisplatin – gold standard with the worst nausea, kidney toxicity, and cytotoxicity (tinnitus). K and Mg wasting may be seen so patients should receive K and Mg solutions. NEVER exceed a total dose of 100 per L^2 daily. Pedmark is a formulation for pediatrics that reduces the risk of cytotoxicity.
Carboplatin – is the least kidney toxic because the dose is based on kidney function and AUC (Calvert equation – AUC * GFR+25) The dose-limiting toxicity is thrombocytopenia (the worst).
Oxaliplatin – The worst with neurotoxicity. Patients have cold intolerance. Even iced coffee can cause a burning sensation in the throat.
Anthracyclines – “Red! – heart – cardiac toxicity”
These agents are derived from Streptomyces. The most common agent from this subgroup is doxorubicin. The red hue comes from alternating aromatic and non-aromatic rings. They were originally used as anti-microbial. They have three mechanisms of action:
- Intercalation
- Inhibit topoisomerase I and II
- Production of free radicals
The orange-red hue can be seen in urine as soon as the first urine after administration and last for 24-48 hours. In patients, the red hue may be seen in the tear ducts.
Anthracyclines can cause cardiac toxicity and have a lifetime maximum dose before the patients are at risk of chronic heart failure.
Anthracenedione – “Antibiotic-Like”
Bleomycin, mitoxantrone, and mitomycin are agents from this subgroup. As with the anthracyclines, they were originally antibiotics, but have very high toxicities.
Mitoxantrone – similar to anthracyclines without free radical mechanism. This means also that it can cause cardiotoxicity. This agent has a blue-green hue to it.
Bleomycin – colorless and dosed in the unit. Common ADRs are rash and fever (pre-medication with APAP), skin hyperpigmentation, and fatal lung disease (dose >400 units). There is a lifetime cap for bleomycin.
Mitomycin – not common, but can cause the hemolytic uremic syndrome.
MISC Agents
Arsenic Trixoide and Tretinoin
There are cell differentiation agents used in the treatment of acute promyelocytic leukemia. They bind to the fusion protein and allow the protein to proceed normally and experience cell death normally.
Arsenic is cardio-toxic, so we must monitor EKG and electrolytes.
These two agents are considered RCRA drugs (Resource Conservation Recovery Act), which means that anything that comes in contact with these two must be disposed of as hazardous drugs.
Tretinoin is teratogenic and can cause dermatologic toxicities and visual disturbances. This is referred to as a retinoid acid syndrome.
Both can cause APL differentiation syndrome, which is total body edema and organ failure. If this happens, steroids should be used to treat it.
Asparaginase – “Chrysanthemum”
The hydrolysis of L-asparaginase leads to a depletion of asparagine, which is important in leukemic cells. This is a targeted effect unlike what we have previously seen. The intention of this agent is the inhibit protein synthesis and apoptosis.
Because it was derived from a microbe, allergic reactions can occur. Glucose intolerance and pancreatitis have been known to occur.
Tracebectedin – “Sea squirt”
This agent binds to the DNA grooves, causing abnormal bending and strand breakage. The main concerns with this agent are hepatotoxicity and fatigue. This is not regular fatigue, it is extreme fatigue that corticosteroid (dexamethasone) is used as premedication to help manage the symptom.
Trifluridine/tipiracil – “Viroptic eye drop”
This is a thymidine nucleoside analog that interferes with DNA synthesis and inhibits cell proliferation. Tipiracil is an agent to help with bio-availability. The most concerning ADR is severe myelosuppression and febrile neutropenia, which can be life-threatening. It is also unique in that it is one of the few oral agents that G-CSF may be needed. The most common ADRs are nausea, diarrhea, and fatigue.