This is the context of the topic chemotherapeutic drugs series. Today is part 4. Topic of discussion for today is resistance to chemotherapeutic drugs and classification of chemotherapy agents. Chemotherapy drugs are of various types. Some are oral, some are given through IV administration.
Here is a quick link to previous topics.
Chemotherapy drugs: Things you need to know
Chemotherapy Drugs for Childhood Cancer Part 2 Basics
Chemotherapy Drugs for Childhood Cancer Part 3 Basics
Resistance to chemotherapeutic agents
Resistance constitutes a lack of response to drug-induced tumour growth inhibition
Primary resistance: No response from very first exposure. e.g., malignant melanoma, renal tumour.
Acquired resistance: During continuation of therapy. Due to adaption of tumour cells or due to mutation in one or more gene.
Mechanism of resistance
1. ↑ Drug efflux via P-glycoprotein transporters, e.g. doxorubicin, paclitaxel, vincristine, etoposide
2. Overexpression of the multidrug resistance protein 1 (MRCP1) → ↑resistance to natural drugs, e.g., vinca alkaloid, anthracyclines.
3. ↓ inward transport, e.g. Methotrexate
4. Insufficient activation of the drug (e.g., Mercaptopurine, Fluorouracil and cytorabine).
5. Increase in inactivation (e.g., Cytarabine and Mercaptopurine)
6. Increased concentration of target enzyme (Methotrexate)
7. Rapid repair of drug-induced lesions (Alkylating agents).
8. Altered activity of target proteins, for example, modified topoisomerase II (Doxorubicin).
How to Overcome Resistance:
1. Use of combination drug therapy using different classes of drugs with different mechanisms of action.
2. With narrowest cycle intervals, necessary for bone marrow recovery.
3. Drugs that reverse multidrug resistance include verapamil, quinidine, and cyclosporine.
Classification of Chemothrapy Drugs:
Cell-Cycle Specific Chemotherapy
These are often given more than one time. This gives the chemotherapy the best chance to kill as many cells as possible.
They may be given in “divided doses” or given at different times. For example, these may be given once a day for 5 days, or every 3 hours for 4 doses. They can also be given as a nonstop infusion. This is an infusion that runs for several hours or more.
Cell-Cycle Nonspecific Chemotherapy
Kill cancer cells at all phases of the cell cycle, including the resting phase. These work best when given in a “bolus dose.” The cells don’t always die right away. A cell may have to go through a few cycles of chemotherapy before it dies. Repeat doses of chemotherapy may be given to keep killing cancer cells.
| CCS | CCNS |
| Tumor with high growth faction | tumor with both and low growth faction |
| Toxicity: Proportional to the duration of exposure; more toxic if given for longer duration | Proportional to the dose |
| Given in smaller repeated dose | Larger few or single dose |
| Dosage: Schedule dependent, given at specific number of days | Dose-dependent, sometimes one maximum dose |
| effective against rapidly growing tumor | Slow-growing tumor |
| Fewer side effects on non-dividing cell | Typically, more side effects as both dividing and resting cells are affected |
Further readings:
Chemotherapy drugs-canadian cancer society Link
Classification of anticancer drugs: A new system based on therapeutic targets Article Link
That’s all for today.
Hope to see you soon.
