Introduction:
Recent developments in anticancer medications have considerably improved cancer patients' quality of life and survival rate. However, an initial positive response to treatment frequently reverses later, resulting in cancer relapse and recurrence. This developed resistance to treatment poses a severe obstacle to anticancer therapy. An example of intrinsic resistance is the inability to elicit an early response.
What Is the Role of Metastasis and Drug Resistance in Cancer Treatment Failure?
Drug resistance, which poses a significant obstacle to the treatment of disease and the overall survival of patients, is described as a decline in a drug's efficacy and potency to deliver therapeutic benefits. The therapy-induced metastasis is due to resistance to anticancer treatments that might appear as local, regional, or distant metastases. The initial response to treatment is frequently poor because malignancies such as kidney cancer, hepatocellular carcinoma (liver cancer), and malignant melanoma (a serious type of skin cancer) may display intrinsic resistance to chemotherapy without prior exposure to anticancer drugs. Adverse outcomes and consequences frequently follow the initial positive treatment response because tumors initially responsive to therapy later stop responding due to the development of acquired drug resistance. Systemic treatments currently used are chemotherapy, immunotherapy, and antiangiogenic medications.
What Is the Difference Between Conventional and Molecular Targeted Chemotherapy?
Targeted chemotherapy aims to achieve a satisfactory treatment response with fewer side effects than other cancer treatments. Drug resistance decreases with more targeting.
Conventional Targeted Drugs: These drugs target cellular proliferation and DNA (deoxyribonucleic acid) replication or are component-based, such as microtubules and topoisomerases (an enzyme that causes changes in the DNA), which are present in both standard and cancer cells. They are more hazardous. They are often delivered in a high dosage.
Molecularly Targeted Drugs: This therapy targets the growth and expansion of cancer cells by blocking their cellular and metabolic pathways. They are significantly less hazardous. Dosages are much lower than the maximum tolerated dose.
However, drug resistance, both innate and acquired, is a problem that affects both conventional and molecularly targeted therapies.
What Are Intrinsic and Acquired Drug Resistance?
Drug resistance may develop due to Intrinsic and acquired resistance:
Intrinsic Drug Resistance:
Factors that contribute to intrinsic resistance are
- Drug breakdown.
- Altered expression or function of the drug target.
- Altered drug transport across the cellular membrane.
- Altered drug metabolism.
- Diminished interaction efficiency between the drug and its molecular target.
- Nuclear receptors or ATP (adenosine triphosphate)-dependent membrane transporters act as intrinsic cellular resistance channels.
- Additionally, metabolic activities carried out by cells, such as ceramide glycosylation, reduce the effectiveness of chemotherapeutic drugs.
Acquired Drug Resistance:
It is affected by genetic or environmental variables that encourage the growth of cancer cell clones resistant to treatment or cause mutations in enzymes engaged in critical metabolic pathways. DNA damage repair proteins improve cross-drug resistance by preventing drug accumulation through
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Reducing the inflow of the drug.
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Increasing the removal of the drug through cell membrane transporters.
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Inactivating any cell cycle regulators that will retain the drug.
It has also been demonstrated that the inactivation of tumor-associated genes (tumor suppressor gene TP53) causes resistance to chemotherapeutic drugs.
What Are the Genetic Determinants of Acquired Drug Resistance?
The following are critical factors in cancer etiology (causes), including intratumor heterogeneity (it refers to the collection of different tumor cells inside a lesion or a tumor), which promotes primary malignancies, distant metastatic lesions, and cancer relapse (recurrence) after therapeutic failure:
- Instability of the genetic content in the body.
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An odd number of chromosomes (each chromosome has DNA which is passed from parent to child).
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Mutations or changes in the normal structure of genes.
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Chromosomal abnormality.
Drug resistance is directly related to
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The level of stability of the genetic material of tumor cells.
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The mechanism of action of a chemotherapeutic drug.
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The dose administered.
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The treatment intervals.
Alterations in the genetic material, such as inactive mutations, can occur in the cancer cells before or during treatment. Cancers intrinsically sensitive to chemotherapy may also contain at least one drug-resistant cell clone, the expansion of which leads to acquired resistance and possible recurrence.
What Are Intrinsic Drug Resistance‑Associated Membrane Proteins?
Drug resistance-associated membrane proteins (DRAMP), also known as membrane transporter proteins, are necessary for multidrug resistance (MDR). These proteins either directly remove drug molecules from cells to reduce intracellular accumulation or indirectly alter the net collection of drugs. There are two significant categories of Drug resistance-associated membrane proteins (DRAMP):
The ATP-Binding Cassette (ABC) Transporter:
This superfamily pumps hydrophobic chemotherapeutic drugs out of tumor cells, reducing net intracellular accumulation and, thus, drug efficacy. They are broadly divided into three groups:
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P-glycoprotein.
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The ATP-binding cassette Glycoprotein -2 group.
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Multidrug resistance-associated proteins (MRPs).
P-glycoprotein- overexpression causes chemotherapeutic failure due to multidrug resistance (MDR) in several types of cancer, including multiple myeloma (plasma cell cancer) and leukemia (blood cancer).
Solute Carrier Transporters:
These enhance chemo-resistance by interfering with the cellular uptake of hydrophilic anticancer agents.
What Are the Different Models to Assess Drug Resistance?
The mathematical and computer models positively correlate the amount of spontaneous genetic changes and chemotherapeutic resistance. This information can modify the administered dose or choose the type of assisted treatment. Other models used prokaryotic (a type of organism that lacks a basic nucleus) paradigms to find mutations in drug-resistant cancer cells and examine how they contribute to treatment resistance.
How to Overcome Drug Resistance?
The route of administration determines an anticancer drug's efficacy and the maximum tolerated dose capable of destroying cancer cells while minimizing side effects. The highest single dose that does not cause adverse effects is the maximum tolerated dose (MTD). The optimal dose for many drugs does not always coincide with the maximum tolerated dose (MTD); thus, determining the optimal amount is problematic.
Metronomic Chemotherapy:
It is a novel and promising drug administration mode involving repeated administration of chemotherapeutic agents at low doses. Metronomic chemotherapy has been beneficial in many cases.
Treatment Holiday:
A treatment holiday is a therapeutic strategy for overcoming drug resistance. The patient's chemotherapy treatment is interrupted to avoid selection for drug-resistant tumor cells, which could lead to cancer recurrence and relapse.
Combinatorial Drug Therapy:
This method will reduce the likelihood of multiple resistant clones developing, particularly in patients undergoing adjuvant anticancer therapy (a treatment initiated after primary treatment like surgery is done to prevent the chance of recurrence of cancer) with micrometastases and low tumors.
Conclusion:
The quality of life and survival rate of cancer patients have significantly increased due to recent advancements in anticancer drugs. Drug resistance seems to negatively impact the new molecularly targeted anticancer treatments, which is a crucial challenge in the therapeutic environment. Drug resistance usually results in a pattern of random mutations rather than a drug-specific effect. The medical community is continuously trying to pinpoint these resistance mechanisms and create brand-new medications that could get around them.
