Cancer, the “King” of all diseases, produces fear in us. Besides being difficult to accept, it causes a condition in which our own cells deregulate themselves becoming “terrorist guerrillas” whose only purpose is to divide and along the way cause organ failure and eventually death. In contrast to autoimmune diseases, in which cells belonging to our own immune system (a hierarchical organized system), also attack our organs for destruction. Malignant cells lack a recognized hierarchy nor are they regulated. As a result, chemotherapy has proven much more successful fighting autoimmune diseases than when used to fighting cancer.
However, not all is gloom and doom when it comes to fighting cancer. In the near future, immunotherapies, biological response modifiers as well as investigative anti-cancer agents combined with cloud-based databases and supercomputers, will result in the introduction of personalized cancer chemotherapies (including for colorectal cancer) that will prove to be highly effective while carrying little side effects. Thus, cancer will become a chronic condition, rather than sometimes a lethal disease. About 66% to 75% of mutations that cause cancer are due to random DNA (copy) errors. The reminder cancers are caused by genetic predisposition, lifestyle, environment, etc.
Normal vs. Cancer Cells
Normal cells are highly regulated. They use a combination of sentinels, checkpoints and repair systems to prevent genetic instability and selection. Moreover, if any of these regulatory mechanisms fail, they have the ability for programmed cell death. Normal cells are mortal. • Cancer or malignant cells develop through a combination of genetic instability and selection. This results in the proliferation of (malignant) cells that have accumulated and advantageous set of genetic aberrations. These aberrations may act alone or in concert to alter the function or expression of cellular components and/or processes. Cancer cells are immortal.
Fig. Legend: All cells eventually go through the cell cycle, a series of sequential events and biochemical processes that allow cells to divide. Clockwise, the cell cycle is divided in sequential stages or phases; (M) mitosis, (G1) gap one, (S) synthesis, and (G2) gap two. Most cells in a given organ are not going through the cell cycle, however. These, non-dividing cells, are not going through the cell cycle, but are arrested at a stage residing near M and G1 phases called gap cero (G0). During G1, the cell grows. Sentries and checkpoint mechanisms ensure that everything is ready for entering the S phase (DNA synthesis). During the S phase the cell grows and most of the DNA is replicated into two identical copies. During G2, the cell grows, while sentries and checkpoint mechanisms ensure that everything is ready for going through the M phase. During the M phase the cell divides separating into two identical new cells (cell division or cytokinesis). Most fast-dividing mammalian cells (including human cells) take about 24 hours to go through the cell cycle. However, there are certain cells, in insect embryos for instance, that take only about 8 minutes to go through the cell cycle while certain mammalian cells may take nearly a year going through their cell cycle. In an average adult human being, between about 50 billion and 70 billion cells die each day due to self-induced cell death (a process known as “apoptosis”). In contrast, children ranging between 8 and 14 years-old, lose about 20 billion to 30 billion cells a day to apoptosis. For every cell death, a new cell must be created thus, in an adult human, there must be at least between 50 billion and 70 billion cells going through the cell cycle to replenish these lost cells.
Tumors vs. Cancer Chemotherapy
A tumor’s growth fraction is the ratio between dividing and non-dividing cells. • Chemotherapeutic drugs are more toxic to tumors with high “growth fraction” than with low “growth fraction.” Solid tumors have a low “growth fraction.” • Disseminated tumors have a high “growth fraction.”
Fig. Legend: Tumor mass residing in the lumen of the ascending colon (colorectal tumor). This solid tumor is an adenocarcinoma that almost occludes the colon’s lumen. The reddish color on the tumor surface, is blood, the tumor bled when the surgeon “touch” it with a fiber-optic probe. The light-colored cauliflower-like structure, at about 5 o’clock, wedged between the tumor and the colon wall, is an abnormal polyp. The tumor diameter is about 2.3 inches.
Cancer Chemotherapy
Drugs vs. poisons • Therapeutic index • Selective toxicity
Drugs and poisons share similar properties. Poisons such as rodenticides, generally have selective toxicity and a low therapeutic index. Therapeutic index is a comparison ratio between the amount of a drug that causes the desired therapeutic effect and the amount of that same drug that causes toxicity (an undesired effect). Selective toxicity is the ability of a drug to target relative specific properties of a microorganism responsible for infection. Sometimes these properties are unique to the microorganism or are more essential to its survival than they are for the host. For instance, antimicrobial drugs such as antibiotics, are drugs that are intended to have selective toxicity against microbes (e.g., bacteria), therefore they kill bacterial cells but not the host’s or the patient’s cells.
Cancer Chemotherapy: Drug Families
Cytotoxic Drugs: • Alkylating agents • Platinum compounds* • Antimetabolites* • Antitumor antibiotics • Mitotic inhibitors • DNA Topoisomerase inhibitors Other Drugs: • Drugs for breast and prostate cancer • Targeted drugs • Immunotherapies (active, passive or hybrid) • Biologic response modifiers (BRM) • Drugs for cancer prevention
Obstacles to Successful Chemotherapy
• Early detection of cancer is rare. Smallest directly detectable tumor is about 1g (or a tumor containing 10 to the power of 8 to 10 to the power of 9 cells). • Chemotherapeutic drugs lack selective toxicity limiting their administration. • Cancer cell killing follows 1st order kinetics. • Cancer cure requires 100% cancer cell kill. • Minimal participation of the immune system in killing cancer cells. • Symptoms disappear before all cancer cells are killed or removed.
Strategies for Achieving Maximum Benefits from Cancer Chemotherapy
• Tumor debulking surgery • Intermittent chemotherapy • Combination chemotherapy Drug combination requirements: ✓ Each drug has to be effective by itself ✓ Each drug should have different mechanism of action ✓ Drugs should have no or minimally overlapping toxicities
Combination Cancer Chemotherapy: (e.g., FOLFOX)
(1) Folinic acid (Leucovorin) — Synergistically enhances the effects of fluorouracil by inhibiting the enzyme thymidylate synthase. (2) Fluorouracil — Fluorinated derivative of uracil inhibiting DNA replication. (3) Oxilaplatin — Generates cross-links inhibiting DNA replication and transcription. (4) Antiemetics — Inhibit chemotherapy-induced nausea and vomiting
