Cancer therapeutic drug guide

Nontopoisomerase inhibitors

The first antibiotic used as an antitumor agent and approved by the US Food and Drug Administration (FDA) in 1964 as such was actinomycin D , obtained from Streptomyces griseus in the mid 1950s. Actinomycin D inhibits the transcription of genes by interacting with a GC-rich duplex, a single-stranded or hairpin form of DNA, and interfering with the action of RNA polymerase.

Mitomycin C was derived in the late 1950s as the second antitumor antibiotic from Streptomyces caespitosus . In tissues, mitomycin C is activated to an alkylating agent and is therefore covered in the following section.

The third prominent antitumor antibiotic in the nontopoisomerase/nonanthracycline category is bleomycin . It was isolated in 1966 from a strain of Streptomyces verticillus. Bleomycin acts by forming complexes with Fe ²⁺ while binding to DNA. Oxidation of Fe ²⁺ subsequently leads to the formation of free radicals, which results in DNA damage. Vascular side effects include flushing and Raynaud’s phenomenon and the most concerning toxicity is pulmonary fibrosis (dose-dependent, commonly seen with cumulative doses greater than 300 units, pulmonary function testing with carbon monoxide diffusing capacity is to be obtained before initiation of therapy and with the onset of any symptoms).

Topoisomerase inhibitors

Among the topoisomerase inhibitory antitumor antibiotics anthracyclines hold a special place for several reasons. They were the first group of cancer drugs that was discovered by a joint effort of a pharmaceutical company (Farmitalia) in collaboration with a research center (Istituto Nazionale dei Tumori in Milan). ^, This effort started in 1960 on a streptomyces strain, Streptomyces peucetius , found near Castel del Monte (Apulia). The new natural antitumor drug was called daunomycin (later daunorubicin), which showed higher efficacy compared with others antitumor drugs in patients with chronic lymphoproliferative diseases. In 1968, with expansion of the joint effort to include Memorial Sloan-Kettering Cancer Center in New York, a new molecule was extracted from a mutated strain of S. peucetius (obtained by treating the microorganism with N-Nitroso-N-methylurea): Adriamycin (later doxorubicin), which showed better activity against tumors in mouse and a greater therapeutic index. It has become the main anthracycline to be used, at least in the United States, for a variety of malignancies. Epirubicin, on the other hand, is used mainly for breast cancer, especially in Europe and idarubicin in the context of induction therapy for acute myeloid leukemia as part of the well-known 7+3 regimen (7 days cytarabine and 3 days idarubicin). For all of these, a key mode of action is inhibition of topoisomerase II alpha, thereby prevention of the relaxation of supercoiled DNA and inhibition of DNA transcription and replication. Additional mechanisms include free radical formation with consequent induction of DNA damage or lipid peroxidation, DNA binding, and alkylation. These two mechanisms are also at play in the myocardium and account for cardiotoxicity. The same holds true for mitoxantrone, which is chemically related to the anthracyclines, an (amino-) anthraquinone that was synthesized in 1979. Unique is its use for metastatic hormone-refractory prostate cancer and in multiple sclerosis.

Currently, the other topoisomerase II inhibitors used clinically is etoposide . Camptothecin , isolated from the Chinese tree Camptotheca acuminate , was used for cancer treatment long before it was identified as a topoisomerase I inhibitor. Owing to its side effects, camptothecin is no longer used clinically. It was replaced by the more effective and safer derivates irinotecan and topotecan .

Cardiovascular toxicities

Anthracyclines are furthermore historically unique because of their unprecedented risk of cardiotoxicity in terms of potency and frequency. In essence, it is only a matter of dose for cardiomyocytes to succumb to anthracyclines. Clinically, two scenarios are differentiated: acute cardiotoxicity, which is a myocarditis-like presentation, and chronic cardiotoxicity, which is a dilated cardiomyopathy-like presentation. Without testing, not many cases declare themselves acutely, even though injury may be present. The inflammation that can be seen in this setting may be classified best as toxic (reactive) myocariditis. Cardiac function assessment (left ventricular ejection fraction [LVEF]) by imaging correlates poorly with cumulative dose and the histologic injury pattern. Heart failure (HF), on the other hand, does seem to have a dose cutoff and follows a decline in cardiac function. Two main mechanisms have prevailed over the years to explain the cardiotoxicity of anthracyclines. The first is the reactive oxygen species (ROS) or iron and free radical theory. Anthracyclines have an affinity for cardiolipin, which brings them in close proximity to the respiratory chain in the mitochondria. In association with anthracyclines cardiolipin is reduced by nicotinamide adenine dinucleotide plus hydrogen (NADH), drawing an electron away from the mitochondrial respiratory chain and subsequently reducing oxygen to form a superoxide anion radical. Further, the addition of an electron to the quinone moiety of anthracyclines leads to the formation of a semiquinone that reverts to the quinone state by reducing molecular oxygen to superoxide anion and its dismutation product hydrogen peroxide (the so called “redox cycling”). A surge in oxidative stress is generated when these products interact with low-molecular iron (Fenton reaction). Anthracyclines may also directly react with ferric iron (Fe3+) to form free radical and alcohol adducts. Collectively these processes lead to oxidative modification of proteins and lipids as well as genomic and mitochondrial DNA damage. Uncoupling of the electron transport chain with impairment of oxidative phosphorylation and adenosine triphosphate synthesis contributes further to mitochondrial dysfunction and damage. Oxidative stress activates a number of stress response pathways, including mitogen-activated protein kinase or extracellular signal-regulated kinase (MAPK/ERK). The phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway can take a protective role, activated, for instance by neuregulin-1 via human epidermal growth factor receptor-2 (HER2) signaling. This explains the syngergistic action in terms of cardiotoxicity when anthracyclines are combined with trastuzumab. An alternative or at least additional mechanism for anthracycline cardiotoxicity that emerged in recent years is the inhibition of topoisomerase II beta in cardiomyocytes. Interfering with topoisomerase function anthracyclines may impair the repair of DNA as well, not only induce DNA damage, as described above.

Among the other antitumor antibiotics, mainly vascular toxicities have been seen. Mitomycin has been associated with thrombotic microangiopathy and HF on occasion (doses > 30 mg/m ² ). Bleomycin can cause abnormal vasoreactivity with Raynaud’s phenomenon and chest pain syndromes as clinical presentations. Bleomycin and cisplatin are the two drugs with the highest risk of drug-induced Raynaud’s phenomenon. Cases of acute ischemic events, including myocardial infarction, have been reported as well.

Patients with cardiovascular risk factors are at higher risk. Pericarditis is uncommon; pneumonitis and pulmonary fibrosis (with pulmonary hypertension) rank among the most concerning side effects (in up to 10% of patients).

Among the topoisomerase II inhibitors, irinotecan can cause vasodilation with hypotension and edema. Cases of thromboembolism have been reported, but it is not one of the cancer drugs that have received consistent and widespread alerts in this regard. Etoposide is mainly known for causing hypotension; cases of myocardial ischemia and infarction have been reported as well.

Prevention and treatment of cardiotoxicity

The outlined mechanisms are important for the prevention and treatment of anthracycline cardiotoxicity. Reduction in the level of oxidative stress is a common denominator among agents that have been shown to be beneficial. These include beta blockers with antioxidant properties, ACE inhibitor and angiotensin receptor blockers (ARBs). ^, Furthermore, statins have been shown to be cardioprotective, possibly related to their antioxidant effects as well as reactivation of the PI3k/AKT kinase pathway. Dexrazoxane has become known as an iron chelator, but also as a strategy to modulate topoisomerase II beta to yield cardioprotective effects.

Mchanism of action (see Fig. 54.1 )

The cytotoxicity of alkylating agents can occur in two ways: conventional alkylation and unconventional methylation. Conventional alkylating agents form an aziridinium ion, which is an electrophilic cyclic ion that induces DNA alkylation either directly or through conversion to a carbonium ion. DNA structural change caused by alkylation blocks replication of new DNA (interstrand crosslink formation disrupts DNA separation) and inhibits transcription to mRNA for protein synthesis, impairing cell function, cell growth, and survival. These effects are amplified when alkylating agents form widespread interstrand crosslinks, inhibiting DNA repair and promoting apoptosis.

These conventional alkylating reactions are generally classified through their kinetic properties as SN1 (nucleophilic substitution, first order) or SN2 (nucleophilic substitution, second order). The first-order kinetics of the SN1 reactions depends only on the concentration of the original alkylating agent (e.g., nitrogen mustards or nitrosoureas), which will decide the rate of formation of the reactive intermediate. The SN2 alkylation reaction ( e.g., alkyl sulfonates) is a bimolecular nucleophilic displacement with second-order kinetics, where the rate depends on the concentration of both the alkylating agent and target nucleophile.

In distinction, nonclassic or unconventional alkylating agents are synthetic inorganic nitrogen compounds that induce methylation of guanine bases, and therefore do not have the DNA crosslinking activity shown for classic alkylating agents.

Nevertheless, the therapeutic and toxic effects of alkylating agents do not correlate directly with the subgroup to which they belong or with their chemical reactivity, because clinically useful agents include drugs with SN1 or SN2, and even some with both characteristics. The differences in their toxicity profiles and antitumor activity are more a consequence of their pharmacokinetics, membrane transport, metabolism and detoxification, lipid solubility, penetration of the central nervous system (CNS), and specific enzymatic reactions capable of repairing alkylation sites on DNA.

Classic alkylating agents

Nonclassic alkylating agents

Cardiovascular toxicities

Alkylating agents can exert cytotoxic effects on the cardiovascular system, often magnified by the comorbid cardiovascular risk factors of an aging population, concomitant cardiotoxic chemotherapies, and radiation. Cardiotoxicity of these agents may range from asymptomatic pericardial effusion to myopericarditis, HF, and arrhythmias (see Table 54.3 ).

Pericarditis and pericardial effusion ( Fig. 54.2 )

Cyclophosphamide can cause pericarditis and pericardial effusion to the point of cardiac tamponade. The most feared complication is a hemorrhagic myocarditis/pericarditis, which occurs more commonly after 1 week of the administration of cyclophosphamide with doses greater than 40 mg/kg/day OR 1.4 g/m ² /day over a minimum of 2 consecutive days. This grave complication presents with HF symptoms, including new dyspnea at rest, elevated jugular venous pulsations, atypical chest pain, and peripheral edema. Tissue pathology demonstrates specific findings of intramyocardial extravasation of blood, fibrin, and fibrin-platelet microthrombi in capillaries. Fibrin strands in the interstitium is the most specific finding for the diagnosis of hemorrhagic myopericarditis. A decrease in QRS voltage can provide a clue. Pericardiocentesis should only be performed if necessary for tamponade.

Busulphan may occasionally cause pericardial and myocardial fibrosis, usually 4 to 9 years later and after a cumulative drug dose of more than 600 mg. Intravenous busulphan may also induce tachycardia, hypertension, or hypotension and LV dysfunction; these complications are not observed after oral drug administration.

Vascular toxicities

Cisplatin (>carboplatin > oxaliplatin) has been associated with vascular events, primarily of two kinds: vasospasm, especially Raynaud’s phenomenon, and thrombosis, including venous and arterial thrombosis. Coronary artery disease does not seem to be a prerequisite for acute coronary events to develop in patients undergoing platinum-based therapies. Intimal erosion secondary to induction of endothelial apoptosis has been suggested as the underlying mechanism (or thromboembolism from an alternate source). Of note, cisplatin levels can remain detectable over decades, indicating a potential long-term risk. Hypertension and renal toxicity are the other main side effects to be aware of for platinum drugs as it pertains to cardio-oncology.

Prevention and treatment of cardiotoxicity

Because most nitrogen mustards have dose-related cardiotoxicity, avoidance of higher doses of these drugs is a key preventative measure.

The relationship between acute toxicity and development of early and late cardiotoxicity is unclear. Clinical trials are required to determine if blocking acute toxicity (e.g., by the use of an ACE inhibitor or ARB) decreases the risk of subsequently developing later cardiotoxicity. All patients who have already developed asymptomatic LV dysfunction or clinical HF, should be treated in keeping with HF guidelines. Of the beta-blockers, carvedilol may have therapeutic advantages over the others, because it has been shown to possess antioxidant properties. Its prophylactic use with alkylating agents is lacking. ^,

Management of arrhythmias should be individualized and decisions on the use of antiarrhythmic drugs or device therapy (implantable or external wearable cardioverter defibrillators) should consider the competing risks of cardiac and cancer-related life expectancy, quality of life, and complications. The diligent monitoring of electrolytes, QT interval on electrocardiogram and the use of QT prolonging agents, acid-base disturbances, and catabolic states are also key besides awareness of the direct arrhythmogenic effects of these drugs.

For complications, such as pericarditis, the use of standard therapy with nonsteroidal anti-inflammatory drugs and colchicine is recommended. Pericardiocentesis or pericardial window surgery should be considered in patients with refractory pericarditis or cardiac tamponade, provided they are not coagulopathic or severely thrombocytopenic.

Hemorrhagic myopericarditis with cyclophosphamide and ifosfamide remains highly fatal and no standard treatment options have proven to reduce mortality. Use of corticosteroids, theophylline, nonselective adenosine antagonist, ascorbic acid, or mechanical circulatory support have been anecdotally reported and must be guided by clinical judgement. No reports were found to demonstrate protection with use of coadministration of mesna.

Emerging preventive strategies

Animal studies have suggested that the cardiotoxic effects of cyclophosphamide are mediated through the toxic reactive aldehyde acrolein, inducing extensive protein modifications and myocardial injury. Myocardial glutathione S-transferase P (GSTP), could prevent cyclophosphamide toxicity by detoxifying acrolein. Although this has only been seen in experimental studies in mice, humans with low cardiac GSTP levels or polymorphic forms of GSTP with low acrolein-metabolizing capacity may be more sensitive to cyclophosphamide toxicity.

Methyl palmitate may be of interest owing to its ability to suppress oxidative stress and to interrupt TLR4/NF-κB signaling pathway with reduction of apoptosis. Similarly, by increasing carboxy-ethylphosphoramide mustard and decreasing acroline concentrations and ROS, N-acetylcysteine also has the potential to prevent cyclophosphamide cardiotoxicity. Other agents that have shown promise as cardioprotectants include curcumine and piperine, oral glutamine, kolaviron, silymarin, blueberry anthocyanins-enriched extracts, green tea extract with hydrochlorothiazide, and many others still under clinical investigation.

Antifolates

Antifolates were the first class of antimetabolites introduced in 1947 with aminopterin inducing complete remission of acute lymphoblastic leukemia. Amethopterin, better known as methotrexate, followed with conserved efficacy but less toxicity. It binds to and inhibits dihydrofolate reductase (DHFR), leading to inhibition of thymidylate and purine synthesis and, subsequently, to the induction of apoptosis.

Methotrexate was rationally designed nearly 60 years ago to potently block DHFR as an antimetabolite, thereby achieving temporary remissions in childhood acute leukemias. DHFR regenerates the reduced form of folate, a requirement for the biosynthesis of purines and thymidylate, which when missing leads to ineffective DNA synthesis and replication. When given in high doses, methotrexate is able to diffuse directly into cells leading to significant toxicity. Therapy is also toxic to nonmalignant cells, although leucovorin is able to bypass DHFR and rescue these cells. The strategy of high-dose therapy followed by leucovorin rescue is commonly used for the treatment of osteosarcoma and hematologic malignancies, especially when there is involvement of the CNS. As with all antimetabolites, methotrexate can cause myelosuppression and mucositis. It can also lead to renal dysfunction, which can be decreased with the use of urine alkalinization. Transaminitis can also be seen. The new generation antifolate pemetrexed is an antimetabolite with activity against certain lung cancers and mesothelioma. It is thought to affect many targets, including thymidylate synthetase, DHFR, and glycinamide ribonucleotide formyltransferase, which ultimately leads to a decreased production of purines and pyrimidines. Folic acid and vitamin B ₁₂ injections are given in conjunction to reduce side effects.

Antipurines and anti(fluoro-) pyrimidines

Antipurines and anti(fluoro-)pyrimidines are analogs to natural deoxynucleotides, competing for the essential role in DNA synthesis, bases, and ribonucleosides. They can be divided into purine analogs (e.g., fludarabine, cladribine ), pyrimidine analog (e.g., cytarabine (ara-C), gemcitabine ), and the fluoropyrimidines (e.g., 5-FU, capecitabine ). 5-FU is readily incorporated into rapidly dividing malignant cells, especially those found within the gastrointestinal tract, explaining the widespread use of 5-FU in gastrointestinal malignancies. 5-FU has multiple mechanisms of action; its metabolite mediates inhibition of thymidylate synthase and 5-FU can also be incorporated into RNA and DNA. 5-FU is clinically administered with leucovorin to increase its antitumor activity. Capecitabine is a prodrug of 5-FU that is selectively activated in tumors overexpressing the activating enzyme thymidine phosphorylase.

5-Fluorouracil is one of the first and most successful designer chemotherapeutics, synthesized in 1957 by Heidelberger and colleagues, as a pyrimidine analog to slow a tumor’s growth by interfering with DNA synthesis. 5-FU-based chemotherapy is the standard of care for adjuvant treatment of stage II and III colorectal cancer (high-risk node-negative and node-positive disease) with a 20% to 30% reduction in mortality. It is also a front-line agent for potentially curable, as well as metastatic, pancreatic cancer, metastatic esophageal and gastric cancer, early stage breast cancer with residual disease after anthracycline-based therapy, and metastatic breast, head, and neck cancers.