ANTI-CANCER DRUGS
INTRODUCTION:
It is estimated that over 25% of the population of the United States will face a
diagnosis of cancer during their lifetime, with more than 1.6 million new cancer
patients diagnosed each year. Less than a quarter of these patients will be cured
solely by surgery and/or local radiation. Most of the remainder will receive
systemic chemotherapy at some time during their illness, In a small fraction
(approximately 10%) of patients with cancer representing selected neoplasms, the
chemotherapy will result in a cure or a prolonged remission.
Principles of cancer chemotherapy:
Chemotherapy aims to disrupt the growth and proliferation of cancer cells by
interfering with their DNA, cell division, or apoptotic pathways. The principles of
chemotherapy include cell cycle specificity, targeting DNA and cell division, the
fraction kill hypothesis, combination therapy, timing and scheduling, adjuvant and
neoadjuvant approaches, and the understanding and management of resistance
and side effects.
Induction for treatment:
Chemotherapy is sometimes used when neoplasms are disseminated and are not
amenable to surgery. Chemotherapy may also be used as a supplemental
treatment to attack micrometastases following surgery and radiation treatment, in
which case it is called adjuvant chemotherapy. Chemotherapy given prior to the
surgical procedure in an attempt to shrink the cancer is referred to as neoadjuvant
chemotherapy, and chemotherapy given in lower doses to assist in prolonging
remission is known as maintenance chemotherapy.
Tumor susceptibility and the growth cycle:
Tumor susceptibility refers to an increased likelihood of developing cancer, while
the tumor growth cycle describes the stages of tumor development, from
initiation to progression.
Treatment regimen and scheduling:
Drug dosage are usually calculated on the basis of body surface area in an effort to
tailor the dosage to each patient.
Log kill phenomenon:
Destruction of cancer cells by chemotherapeutic agents follows first-order
kinetics that is given dose of drug destroys & constant fraction of cells. The term
log kill is used to describe this phenomenon. For examples diagnosis of leukemia is
generally made when there are about 10° (total) leukemic cells Consequently
treatment leads to 4 09999% KI then 0.001 of 10 remain. This is defined as a 5-100
kill (reduction of 10 cells). At this point the patient becomes symptomatic and the
patient is in remission reduction in the number of microorganisms results in a cure
because the immune system can destroy the remaining bacterial cells. However,
tumor cells are not as readily eliminated and additional treatment is required to
totally eradicate the leukemic cell population.
2. Pharmacologic sanctuaries:
Leukemic or other tumor cells find sanctuary in tissues such as the central nervous
system (CNS) where transport constraints prevent certain chemotherapeutic
agents from entrance. Therefore, a patient may require irradiation of the
craniospinal axis or intrathecal administration of drugs to eliminate leukemic cells
at that site. Similarly, drugs may be unable to penetrate certain areas of solid
tumors.
1. Treatment protocols:
Combination chemotherapy is more successful than single-drug treatment in most cancers for
which the chemotherapy is effective.
a. Combination chemotherapy:
Cytotoxic agents with different toxicities, and with different molecular sites and
mechanisms of action, are usually combined at full doses. This results in higher
response rates, due to additive and/or potentiated cytotoxic effects, and
nonoverlapping host toxicities in contrast, agents with similar dose-mining
toxicites, such as myelosuppression, nephrotoxicity, or cardiotoxicity, can be
combined safely only by reducing the doses of each
b. Advantages of combinations:
The advantages of combination chemotherapy are that it
1) provides maximal cell killing within the range of tolerated toxicity.2) is effective
against a broader range of cell lines in the heterogeneous tumor population, and
3) may delay or prevent the development of resistant cell lines.
c. Treatment protocols:
Many cancer treatment protocols have been developed, and each is applicable to
a particular neo-plastic state. They are usually identified by an acronym. For
example, a common regimen called R-CHOP, used for the treatment of non-
Hodgkin lymphoma, consists of rituximab, cyclophosphamide,
hydroxydaunorubion (doxorubicin) Oncovin vincristine), and prednisone Therapy
is scheduled intermittently to allow recovery or rescue of the immune system,
which is also affected by the chemotherapeutic agents, thus reducing the risk of
serious infection.
RESISTANCE AND TOXICITY WITH CHEMOTHERAPY:
Resistance and toxicity are two major challenges in chemotherapy, significantly
impacting treatment effectiveness and patient outcomes. Here's a breakdown of
both
1. Chemotherapy Resistance
Definition: Resistance occurs when cancer cells adapt to withstand the effects of
chemotherapy drugs, making the treatment less effective or even ineffective.
Types:
Intrinsic resistance: The tumor is resistant before treatment begins.
Acquired resistance: Develops over time after exposure to chemotherapy.
Mechanisms:
Drug efflux: Overexpression of proteins (e.g., P-glycoprotein) pumps drugs out of
cells.
Drug inactivation: Enzymes within cancer cells degrade or modify drugs.
DNA repair: Enhanced repair of DNA damage caused by chemotherapy.
Evasion of apoptosis: Cancer cells bypass programmed cell death.
Tumor microenvironment: Factors like hypoxia and stromal cells may protect
tumor cells.
2. Chemotherapy Toxicity
Definition: Toxicity refers to the harmful side effects of chemotherapy on healthy,
rapidly dividing cells.
Common toxicities:
Hematologic: Anemia, neutropenia, thrombocytopenia.
Gastrointestinal: Nausea, vomiting, diarrhea, mucositis.
Neurological: Peripheral neuropathy.
Cardiotoxicity, nephrotoxicity, hepatotoxicity depending on the drug.
Fatigue, hair loss, fertility issues.
Management:
Dose adjustments.
Supportive therapies (e.g., antiemetics, growth factors).
Switching drugs or combining therapies to minimize side effect.
Tyrosine kinase inhibitors:
The tyrosine kinases are a family of enzymes that are involved in several
important processes within a cell, including signal transduction and cell division.
[Note: At least 50 tyrosine kinases mediate cell growth or division by
phosphorylation of signling [Link] have been implicated in the
development of many neoplasms.]
IMMUNOTHERAPY
Immunotherapy with intravenous immune checkpoint inhibitors is a rapidly
evolving option for cancer treatment.
MOA: The goal of immune checkpoint inhibitors is to block the checkpoint
molecules, such as the programmed death (PD-1) receptor, that normally help to
keep the immune system in check. By blocking these molecules, the immune
system is better able to attack the tumor and cause destruction .
DRUGS:The two most commonly used checkpoint inhibitors are pembrolizumab
and nivolumab.
The adverse reaction profiles of these agents consist of potentially severe and
even fatal immune-mediated adverse events. This is because turning off the
immune checkpoints allows attack of the tumor, but can also lead to unchecked
autoimmune response to normal tissues. Adverse events include diarrhea, colitis,
pneumonitis, hepatitis, nephritis, neurotoxicity, dermatologic toxicity in the
form of severe skin rashes, and endocrinopathies such as hypo- or
hyperthyroidism.