Fig. 1.1
The “sliding doors concept”: a patient with cancer and a cardiovascular pathology may undergo different treatment pathways that, if not led in coordination by the specialists, may lead both to delay in cancer treatment and to enhanced cardiotoxicity
The meaning of this concept is that the management and the outcome of the patient may dramatically differ if the approach to the patient that is suffering both of a cardiac condition and a cancer is not a coordinated approach between the two specialties and it is prevailing one or the other.
If the patient has a prevalent cardiac approach, probably he/she will be cured for the cardiac condition in an aggressive but time-consuming way while the oncologic approach will be delayed or not fully performed, assuming that the possible cardiac toxicity of cancer therapy may compromise the results of the cardiac treatment. The treatment of the cancer may not be correctly and fully exploited, reducing the possibility of a complete cure of the malignancy.
If the patient is followed from the oncologic point of view, it is possible that the cardiac problem may be neglected. He/she can be treated with a cardiotoxic agent and/or by radiotherapy with resulting development of cardiac damage and clinic consequences. The cancer treatment may lead to a complete remission of the malignancy, but the patient will develop a cardiomyopathy and will have a subsequent history of heart failure.
But if the patient is managed in a coordinated way by the cardiologist and the oncologist, he/she can be treated simultaneously for both pathologic conditions in the better manner possible, reducing the possibility of cardiotoxic events and improving the prognostic outcome of the malignancy.
1.4 Brief Historic Data on Chemotherapy
The chemotherapy era begins after World War II with the casual observation of bone marrow suppression by nitrogen mustards. In the years from 1950 to 1960 began trials and therapeutic use of alkylating agents derived from nitrogen mustards, antifolates, vinca alkaloids, platin derivatives, anthracyclines, and taxanes. Hormone derivative and hormone suppressor were demonstrated active in cancer suppression when these neoplastic diseases are hormone dependent, like the sexual organs. After the use of single agents began the use of combination treatments by the association of different drugs. An impressive breakthrough in chemotherapy was made after the impressive progression of the knowledge of cell biology and the recognition of intimal regulatory growth and function of cellular mechanisms by target therapy from the 1980s, with tyrosine kinase inhibitors and with monoclonal antibodies.
1.4.1 The Beginning
The first time that the term “chemotherapy” appeared was before 1900, a term that was coined by Paul Ehrlich (1854–1915), a German bacteriologist.
He synthesized and tested hundreds of organic arsenical compounds for the treatment of syphilis, discovering arsphenamine (Salvarsan), the first synthetic chemical treatment of a human parasitic disease.
The first drug used for cancer chemotherapy was probably a casual discovery.
The sulfur mustards, commonly known as mustard gas (1,5-dichloro-3-thiapentane), are not originally intended as chemotherapeutic agents but are a class of cytotoxic, vesicant chemical warfare agents that act by forming large blisters on the exposed skin.
Mustard gas was used as a chemical warfare agent during World War I and World War II and is still part of the chemical armaments of some countries.
The first-known use was done by the German army during World War I in July 1917 against British soldiers near Ypres (for this reason it is also named yprite).
Mustard gas was lethal in only about 1 % of cases.
Traditionally it is narrated that during a military operation during World War II, a group of seamen were exposed to mustard gas as a result of an explosion in the harbor of Bari, Italy. After some weeks these seamen developed marrow and lymphoid hypoplasia, and this finding gave to the researchers the idea to use nitrogen mustard analogues to treat lymphomas. After this observation probably began the use of alkylating agents, such as mechlorethamine and busulfan, for cancer treatment [7].
1.4.2 Nitrogen Mustard Derivatives
The two famous pharmacologists Louis S. Goodman and Alfred Gilman began to study the potential therapeutic applications of these chemical agents. Profound lymphoid and myeloid suppression had been observed during autopsy observations of people exposed to mustard gas.
The supposition was that this agent, acting on the rapidly growing white blood cells, might have a similar effect on cancer and on lymphomas.
In an animal model of mice treated with mustard agents, they could demonstrate the possibility to treat lymphomas. Successively they administered mustine (the prototype nitrogen mustard anticancer chemotherapeutic) to a patient with a non-Hodgkin’s lymphoma observing a consistent reduction in the patient’s tumor. The effect lasted only for a short time, but this was the first demonstration that cancer could be treated by pharmacological agents.
Alkylating agents were among the first drugs for treating cancer to enter the clinical field and are still used in the treatment of some leukemia and solid tumors.
Shortly after, pharmacology and chemical researchers began to look for other substances that might have similar curative effects against cancer.
1.4.3 Antifolates
Folic acid is a key component in the growth process of microbes that are able to produce it from precursors. The sulfanilamides are antibiotics acting against the process of folic acid production, being similar in its chemical structure to one of the “precursors” and stopping its production. Without folic acid bacteria cannot replicate.
Also human cells use folic acid in their chemical DNA producing processes, and the modification of these processes related to folic acid interferes with the process of cell division and growth that could be slowed or stopped.
Based on this assumption began the study of the chemical pathways by which human cells form nucleic acids and the possibility to interfere with it was investigated.
The effects of folic acid on leukemia patients were studied in the first years after World War II.
These experiences led to one of the first examples of rational drug design with the use of the folate analogues aminopterin and amethopterin (well known as methotrexate). These substances were antagonizing folic acid, blocking the function of folate-requiring enzymes.
These became the first drugs to induce remission in children with ALL that, although of brief duration, demonstrated that antifolates could suppress proliferation of malignant cells.
1.4.4 Vinca Alkaloids
A folk remedy used for centuries, the Madagascar periwinkle was discovered in the 1950s to contain many biologically active alkaloids. The use of a vinca preparation in mice with leukemia showed myelosuppression and the prolongation of their survival. The effect of the vinca alkaloids is due to their inhibition in microtubule polymerization, a process required for cell division.
1.4.5 Cisplatin
In the 1960s, it was observed that the electrolysis of a platinum electrode produced cisplatin, inhibiting the reproduction of Escherichia coli forming irreversible cross-links with bases in DNA. The drug was tested and demonstrated to be effective on sarcomas implanted in rats.
1.4.6 Anthracyclines
The anthracyclines are a family of the most effective anticancer treatments ever developed and are active against more types of cancer than any other class of chemotherapy agents. Daunorubicin was the first anthracycline discovered. It is produced naturally by Streptomyces peucetius, a species of Actinobacteria. Shortly after doxorubicin (Adriamycin) was developed.
One of the main adverse effect of anthracyclines is cardiotoxicity that was discovered in 1967 [8] and that considerably limits their usefulness.
This was the first documented example of cardiotoxicity induced by chemotherapy
1.4.7 Taxanes
Also in the 1960s, Taxol was discovered, a substance extract from the bark of the Pacific yew tree that could be used to contrast cancer growth. This drug is another example of the hundreds of natural substances used for centuries to treat different diseases.
The taxanes are diterpenes produced by the plants of the genus Taxus (yews). They were first derived from natural sources, and in the following years, some have been artificially synthesized.
Taxanes have been used to produce various chemotherapy drugs. The principal mechanism of the taxane class of drugs is the induction of microtubule malfunction, essential to cell division, obtained by stabilizing GDP-bound tubulin. Unlike taxanes, the vinca alkaloids destroy mitotic spindles; taxanes and vinca alkaloids are therefore named for their action, spindle poisons or mitosis poisons, also if their action differs in some ways. It seems that taxanes are also radiosensitizing.
1.4.8 Hormones
In the late 1800s and early 1900s, scientists working on hormones and their effects on the body began also to discover connections between hormones and some tumors. In the 1930s there were first demonstrations that breast cancer could have some improvement by removing ovaries and prostate cancer by castration or by administration of estrogens in the dog.
The modification of the endocrine system through exogenous administration of specific hormones, particularly steroid hormones, or through drugs which inhibit the production or activity of hormones is the theoretical basis for hormone cancer therapy. The modification of the levels or activity of certain hormones that can be powerful drivers of gene expression in specific sensible cancer cells can obtain the cessation of growth or even cell death in some cancers of hormonally responsive tissues like the breast, prostate, endometrium, and adrenal cortex.
1.4.9 Present Days
Since the beginning of chemotherapy, many other drugs have been developed to treat cancer.
In the period from 1955 to 1967, over 114,000 synthetic and pure natural products were tested, in order to look for more active and better-tolerated chemotherapy agents.
However, the principles and limitations of chemotherapy are still the same after being discovered by the early researchers.
1.4.10 Combination Therapy
Considering the limitation of the single drugs, in 1965 the concept of combination chemotherapy, a strategy until now used in antibiotic therapy for tuberculosis with a combination of drugs, each with a different mechanism of action, began to be applied. This concept is related to the possibility that cancer cells become resistant to a single agent: by using different drugs concurrently, it would be more difficult for the tumor to develop resistance to a combination treatment.
The POMP regimen composed of the simultaneous administration of methotrexate, vincristine, 6-mercaptopurine, and prednisone induced long-term remissions of acute lymphoblastic leukemia in children.
This approach was extended to the Hodgkin’s and non-Hodgkin’s lymphomas in 1963 with the MOPP regimen, a combination of nitrogen mustard, vincristine, procarbazine, and prednisone.
1.4.11 Adjuvant and Neoadjuvant Therapy
Another impressive progress in chemotherapy was the successive spread of adjuvant therapy. This is referred to an additional treatment, usually given after surgery when the detectable disease has been removed, but a statistical risk of relapse is still present due to an occult disease. The rationale of this strategy is a treatment for a risk, rather than for an overt disease, accepting that some patients will be treated also if already cured by their primary surgery. The aim of adjuvant treatment is to improve disease-specific and overall survival. Adjuvant chemotherapy and radiotherapy are often used following surgery for many types of cancer, including colon cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, and some gynecological cancers.
Neoadjuvant therapy, both with chemotherapy and radiotherapy, is, on the contrary, given before the main treatment with the aim to reduce the size of the tumor so to facilitate more effective surgery.
1.4.12 Autologous Bone Marrow Transplantation
The possibility to administer doses of chemotherapy previously considered to be lethal was obtained by the procedure of patient’s bone marrow harvesting. It consists of the administration of very high doses of chemotherapy, followed by the transplantation of the harvested bone marrow into the patient a few days later.
The benefits of high doses of chemotherapy supported by autologous bone marrow transplant have been demonstrated for patients with Hodgkin’s disease who had failed therapy with conventional combination chemotherapy. However, autologous bone marrow transplantation continues to be used as therapy for a number of incurable hematologic malignancies, while, due to a much reduced benefit in the face of a high risk, it is no longer used for solid tumors.
1.4.13 Supportive Care During Chemotherapy
As it is obvious from their action mechanisms, cancer chemotherapy drugs are essentially powerful poisons.
Patients receiving these agents are suffering from severe acute and long-term side effects, limiting the doses which could be administered and the beneficial effects, compromising the quality of life, and damaging other body functions like bone marrow, kidney, and liver function and different kinds of cardiac functions.
The possibility to manage and contrast these toxicities is crucial for the success of cancer chemotherapy.
Support with platelet and red cell transfusions as well as broad-spectrum antibiotics in case of infection during the period of bone marrow suppression is essential to allow the patient recovery.
Chemotherapy-induced nausea and vomiting (CINV of the literature), while not directly causing patient deaths, is intolerable at higher doses. The development of new nausea-preventing drugs (the prototype of which was ondansetron) has been a great progress.
1.4.14 Target Therapy
Oncology seemed to have reached top results, without possibility of further progress; however, in recent times the molecular biology development has permitted to approach the explanation of the intimate cellular mechanisms underlying cancer.
The study of cell biology discovered new signaling networks that regulate cellular activities such as proliferation and survival, radically altered in cancer cells. These alterations have a genetic basis caused by a casual somatic mutation.
Understanding the biochemical and biomolecular cell functions and advances in the techniques to modulate its mechanisms allowed researchers to understand the core of cancer and gave the possibility of new interventions in its suppression.
Previous chemotherapeutic agents often had been discovered by chance or by inhibiting the discovered metabolic pathways crucial to cell division. From present days it could be hoped in new treatments particularly specific for the specific cancer cell inhibition.
1.4.15 Tyrosine Kinase Inhibitors
Imatinib mesylate is a small molecule inhibiting a signaling molecule kinase. From many years it has been recognized in chronic myelogenous leukemia (CML), a genetic abnormality due to chromosomal translocation that is responsible for the generation of an abnormal fusion protein, the BCR-ABL kinase. This protein leads to uncontrolled proliferation of the leukemia cells. Imatinib specifically inhibits this kinase, and this modification can help to control the disease, without important effects on normal cells. The first demonstration of the possibility to achieve a complete remission in the large percentage of patients (>90 %) with chronic-phase CML with the use of this small molecule was obtained by Brian Druker [9].
This is a classic example of targeted therapy, and its pharmaceutical discovery was derived from the programmed research of the industry of a molecule specific with that specific target.
1.4.16 Monoclonal Antibodies
For every given substance, it is theoretically possible to create monoclonal antibodies specifically binding to it. Monoclonal antibodies (mAb or moAb) are specific identical antibodies that are produced by clones of a single parent immune cell of a specific type. They have been used initially for diagnostic purpose in the detection of a substance (like biologic variables) and then for purifying or specifically inhibiting a substance, becoming an important diagnostic or therapeutic tool in biochemistry, molecular biology, and medicine. The generic name of drugs constituted of monoclonal antibodies conventionally ends in the suffix “-mab”.
In the past monoclonal antibodies were obtained from mice: this derivation caused as a rule severe allergic reactions during the administration in man, and they were also rapidly removed from circulation.
< div class='tao-gold-member'>
Only gold members can continue reading. Log In or Register to continue
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
