Tom And Jerry Classic Collection Volume 2 Dvd

[Tamar Navratil]

Tomand Jerry: The Classic Collection is a series of Region 2 DVD sets released by Warner Home Video. The sets include selected Tom and Jerry shorts on each volume. These DVDs are available in 6 double-sided DVDs (issued in the United Kingdom) and 12 single-layer DVDs (issued throughout Europe and Australia). The DVDs in the UK were re-released as "Collector Editions", which were Digipak versions with 2 Volumes inside.

None of the cartoons in the set have been restored; all were sourced by TV prints created by Turner Entertainment in the 1990s for Cartoon Network and Boomerang airings. Some of the cartoons in these DVD sets are censored due to perceived racial stereotypes.

Shorts produced in CinemaScope are presented in pan and scan for showing on the 4:3 aspect ratio television screen, except for remake shorts The Egg and Jerry, Tops with Pops and Feedin' the Kiddie. These shorts are not in anamorphic widescreen, like the American Spotlight collections; instead, they are in a 4:3 windowbox format and appear to be sourced from the laserdisc set (The Art Of Tom and Jerry) or are an early release of the copies found on the spotlight releases.

At first glance, the processes of anticancer drug development and environmental risk assessment may not seem to have much conceptual overlap. However, there is a strong common thread based upon the need to make decisions regarding allowable human exposure limits. In both cases, heavy reliance is placed upon interspecies toxicological comparisons.

Risk assessment is based upon both mathematical models and experimental data. For example, the data might be the incidence of tumor formation in rodents following controlled laboratory exposures to a toxin. The role of the model is to predict the incidence of carcinogenesis in humans under a variety of occupational and/or environmental exposure conditions. The weakest link in this process is model validation. Due to ethical considerations, it is not usually possible to administer precise amounts of toxic chemicals to humans. If a human population develops an unusual form of cancer, epidemiologic detectives might be able to trace the source to a particular chemical. The human exposure data are estimated retrospectively in whatever fashion possible, but the uncertainty in these calculations is a major hurdle in quantitative analyses. Once a specific chemical becomes suspect, it would be possible to do a set of quantitative experiments in animals.

Even if we accept these examples with their imprecise estimates of human exposure, the total data base for model validation is very small. Yet a variety of needs forces us to accept these models as the basis for major prospective decisions that have an impact upon the health of citizens and the economic well-being of corporations and communities.

The preclinical toxicology phase of drug development shares some of the same facets as the safety testing of industrial pollutants or other potential environmental contaminants. For example, animals are used to determine a lethal dose, such as the lethal dose for 10% of the animals tested (LD10). That estimate is then used to determine safety in humans. Perhaps the single largest difference between the development of anti-cancer drugs and the assessment of risks from environmental contaminants is that direct experimental evidence is obtained in humans that can be (rapidly) compared with data from animals.

The treatment of a life-threatening disease requires a rather different set of risk-to-benefit decisions than considerations of maximally allowed pollutants. The drugs used for the treatment of cancer have narrower safety margins than those used for most other diseases. In general, the ratio of a therapeutic dose to a toxic dose approaches unity.

Drug development consists of a progression of steps (Table 1) that starts with the discovery of a new compound and ends with a clinical determination of therapeutic utility. To begin human testing, a safe starting dose is needed. Establishment of a safe starting dose is one of the chief functions of preclinical toxicology studies. As reviewed by Grieshaber and Marsoni (1986), the current preclinical toxicology protocol for anti-cancer drugs provides the basis for a safe starting dose, tailored to potency in rodents. The human starting dose is 1/10 of the mouse LD10, expressed on a milligrams/square meter basis. Prior to human testing, this dose is confirmed in a second species.

After the starting dose has been evaluated in patients, subsequent doses are escalated. Although there is always therapeutic intent when an anti-cancer drug is given to patients, the major scientific goal of initial clinical trials is to determine the acute, reversible toxicity. The endpoint of these phase I trials is called the maximum tolerated dose, or MTD. The MTD is used to establish the dose for more detailed efficacy studies in phase II testing. The procedure used for dose escalation must achieve a balance between the desire to escalate slowly enough to be safe and the desire to escalate fast enough to be efficient. The most commonly used procedure is known as the modified Fibonacci scheme (Goldsmith et al., 1975). The initial escalation is rapid (100%, or doubling of the dose); subsequent escalations narrow down until the 30-35% range is reached (Figure 1).

How well does this strategy work? In Figure 1, the ratio of (human MTD)/(mouse LD10) is presented for a series of anticancer drugs (Collins et al., 1986). First, it is worth noting that this particular collection of interspecies toxicology data, although not exhaustive, probably exceeds any comparable compilation for environmental contaminants or other human toxins. Rather than focusing on specific drugs at this stage, it is helpful to get some appreciation of the range of variation. It could be argued that there is considerable variation, even though the average is quite reasonable. It might also be reasonably argued, however, that this level of agreement is adequate for comparative purposes. A number of factors provide motivation to probe further. For example, patient safety might be improved by a better understanding of the sources of this variation. Also, the efficiency of early clinical testing might be raised if the toxicologic variation could be related to measurable determinants, such as plasma levels.

What are possible explanations for this variation in toxicity between mouse and man? Table 2 lists three possibilities: (1) differences in drug metabolism, elimination, and binding; (2) exposure time differences; and (3) target cell sensitivity differences.

Elimination rates determine the drug exposure, or C T, the area under the concentration versus time curve. The concept of C T with regard to drug toxicity originated during World War I (Prentiss, 1937). German pharmacologists observed that mustard agents are equally toxic whether a high concentration is inhaled for a short time or a low concentration is inhaled for a long time. The essential feature is that the C T is the determinant of effect rather than the absolute concentration itself.

Most toxicologists have presented their dosing information in terms of milligrams/kilogram. Based upon the relationships between body surface area and body weight (Freireich et al., 1966), it is possible to interconvert dosing data between milligrams/square meter and milligrams/kilogram. For mice, the relationship is 1 m2 = 3 kg. For humans, it is 1 m2 = 37 kg. Empirically, either set of units can be used to present raw data. The use of body surface area has a distinct advantage, however, when toxicity comparisons are made across species. The physiological determinants of elimination rates (such as glomerular filtration rate or organ blood flow) tend to be highly correlated with body surface area. Thus, if the dose is expressed in milligrams/square meter and elimination rates (milliliter/minute/square meter) are identical in mice and men, then the drug exposure (C T) will be the same in both species at the same dose. On the other hand, if the dose is expressed in milligrams/kilogram, the dose in humans that produces equal C T will be 1/12th the mouse dose, because a correction must be made for body surface area differences. The factor of 12 is simply the ratio of body surface area constants, 37/3.

Freireich et al. (1966), Skipper et al. (1971), and Schabel et al. (1983) have reported that with many anticancer drugs, toxicity observations carry across species on a milligram/square meter basis, as long as schedules are similar. They also were aware, however, that there are exceptions and that more complete exposure parameters such as C T or plasma pharmacokinetics allow more useful comparisons of toxic or therapeutic responses from experimental and clinical studies.

Doxorubicin appears to be an example of metabolism/elimination differences. The MTD in man is fivefold greater than the LD10 in mice, on a milligram/square meter basis. Yet, as shown in Figure 2, there is considerable agreement between blood levels measured at equitoxic doses. It appears that humans are more tolerant than mice due to a higher clearance (milliliters/minute/square meter) for doxorubicin.

The second factor of possible importance is a difference in exposure times. For some drugs, there are threshold concentrations or time dependencies that are related to toxicity and/or mechanisms of action. For drugs with equal clearance values in mice and humans (milliliters/minute/square meter), Skipper and colleagues (1971) have made the point that a bolus dose of equal milligrams/square meter generally produces rather different time courses in mice and man (Figure 3). If there is a threshold for action and a critical exposure time, where the threshold lies can give major differences in species response. For example, if the threshold in Figure 3 is set at 10-6 M, there is no effect in man. If the threshold is set at 10-7 M, however, the duration of effect is much longer in man than in mice. Note that the time course for doxorubicin (Figure 2) is an exception to the generalized pattern.

3a8082e126