Dog Parvo Symptoms

Time-dose and fractionation refers to the schedule of the radiation treatments to be administered. The graph above refers to the rate of tumor control and late complications (vertical axis) at a given total administered dose (horizontal axis). The probability of tumor control obviously increases with a higher total dose, but so does the probability of late complications. One way to resolve this problem – and decrease the rate of late complications – is to administer the total dose multiple small doses at one time. This is referred to as dose fractionation. Fractionation of the total radiation dose, or fractionation protocols, was first developed for human medicine as far back as 1920. By the 1950s, it was being used in veterinary medicine, but in a coarser fashion because of the need for anesthesia at every treatment. While veterinary fractionation schemes still tend to be slightly coarser than those used in human medicine, they have improved significantly with the advent of safer anesthetic protocols. The basis principle behind fractionation can be found in the 4 R’s in radiation therapy: Repair, Re-assortment, Re-population and Re-oxygenation.

Repair: Radiation’s attack on cells appears to be primarily on the DNA level. Radiation damage to DNA can be described in a grossly simplified manner by limiting the discussion to two patterns: single strand breaks and double strand breaks. One single strand break is usually relatively easy to repair by the cell. Two, separate, single strand breaks are each similarly and individually repaired. However, the closer the two breaks are to one another, the more likely the chromosome or chromatid will break into two separate pieces, becoming a double strand break. A detached piece of chromosome or chromatid can either rejoin the strand in its normal position or in an incorrect one, leading to an aberration. Thus, double strand breaks are less likely to be correctly repaired and may result to lethal damage.

Sublethal damage usually refers to single strand breaks that can easily be repaired – as long as a second break does not occur too close by before repair is completed. When a small dose of radiation is administered, sublethal damage occurs in multiple areas in a cell. If the cell is not saturated by this damage, and has enough time to repair itself before cell division (or before the next radiation dose), the cell will survive.

Slowly proliferating cells are better able to repair sublethal damage, making them less susceptible to radiation cell death following a fractionated protocol. The time required for completion of the repair is a minimum of 6 hours for most tissues, but tissues from the nervous system usually require additional time. Although all cells will achieve a certain degree of repair during this interval, more slowly proliferating cells will survive than fast proliferating cells. Re-assortment: Cells have varying radio-sensitivities at different phases in their cycle. As a rule, cells tend to be most sensitive during mitosis and the G2 phase of their cycle, and most resistant during the S (synthesis) phase. During the interval between treatments, some cells in the resistant S-phase will cycle through to more sensitive phases, becoming more susceptible to cell death on the following treatment. Again, this is more likely to affect fast proliferating cells, resulting in an increased cell kill of the more rapidly dividing cells.

Re-population: Some cells survive mitosis between treatments and continue to multiply, making up for at least part of the radiation-induced cell loss. In this instance, the fast proliferating cells regain more cell population than the slowly proliferating cells, and the tissues they make up are more likely to survive. Since tumors generally consist of fast proliferating cells, the likelihood of tumor control is greatly decreased when the radiotherapy schedule is interrupted – and, thus, why such interruptions are strongly discouraged.

Re-oxygenation: Hypoxic tissues (those lacking oxygen) are more radio-resistant than
well-oxygenated ones. Tumor cells often have multiple areas of poorly oxygenated tissue due to a poor vascular system, and longer diffusion distances, causing tumor necrosis.

Radiation (ionizing photons) interacts with water molecules to form highly reactive free radicals that are responsible for breaking strong chemical bonds, most importantly in DNA, leading to eventual cellular destruction. It appears that oxygen “fixes” or secures the radical damage on the DNA, making it unrepairable. Therefore, the damage is less likely to be ‘fixed’ if the environment lacks oxygen, rendering cells in hypoxic areas more resistant to radiation. As the surrounding cell population decreases following cell death, hypoxic areas will re-oxygenate between doses in a fractionated course of treatment. This re-oxygenation causes some initially resistant cells to become more sensitive to the next dose administration, which may improve tumor control by decreasing the radio-resistance caused by hypoxia. Since normal tissues are generally well oxygenated, re-oxygenation does not affect their cells.