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Experimental Evaluation of Potential Anticancer Agents

XII. Quantitative Drug Response of the SA180, CA755, and Leukemia L1210 Systems to a "Standard List" of "Active" and "Inactive" Agents

Kettering-Meyer Laboratory [Affiliated with Sloan-Kettering Institute] Southern Research Institute, Birmingham, Alabama

The quantitative drug response of the Sa180, Ca755, and L1210 systems to a so-called standard list of "active" and "inactive" agents (some 80 in number) has been determined. This study included (a) careful toxicity determinations using nontumor-bearing Swiss and BDF₁ mice and qd 1–7 and qd 1–11 day dosage schedules with extended observation for mortality after cessation of drug administration and (b) use of a "specificity" test as an added criteria of "activity."

The following general comments and conclusions based on analysis of data obtained are listed:

(a) If the dosage schedules are the same, there is no over-all difference in the sensitivity to "drug toxicity" between random-bred Swiss mice and BDF₁ mice [mean ratio (LD₁₀, qd 1–7, Swiss)/(LD₁₀, qd 1–7, BDF₁) = 0.99].

(b) The mean difference in LD₁₀'s for a large number of drugs obtained using the qd 1–7 day and qd 1–11 day dosage schedules (BDF₁ mice) was about what would be expected [mean ratio (LD₁₀, qd 1–7, BDF₁)/(LD₁₀, qd 1–11, BDF₁) = 1.56].

(c) The over-all results obtained on assessment of the present list of drugs using the Ca755 system and two different dosage schedules (qd 1–7 days, tumor assessment day 12; and qd 1–11 days, tumor assessment day 12) indicated no marked technical advantage of one schedule over the other. The advantage in screening efficiency of the use of a similar dosage schedule for the Ca755 and Sa180 systems in the view of the general similarity in LD₁₀'s obtained with BDF₁ and Swiss mice is apparent.

(d) The importance of toxicity data obtained in nontumor-bearing animals, where prolonged observation for delayed mortality can be made, is emphasized. The median day of death following an LD₉₀ (BDF₁ mice, qd 1–11 days, observation 1–21 days) of a considerable number of so-called active agents was on the average 10 days (range 2–19 days). This phenomenon can most assuredly result in selection of "false positives" in Sa180, Ca755, and L1210 systems.

(e) The optimal dose (dose providing for maximal increase in life span) for the list of agents showing activity against the L1210 system (CCNSC protocol) is, in general, rather remarkably close to the LD₁₀ (BDF₁, qd 1–11, observation 1–21 days). The mean ratio of the optimal dose (qd 1–15 days or until death) to this LD₁₀ was 1.02, the median 0.99, and the range 0.3–2.0.

(f) About 78 percent of the agents listed as "active" on the so-called standard list were also "active" by seemingly reasonable, but arbitrary, quantitative criteria employed herein. Almost none of the "inactives" in this list showed activity against Sa180, Ca755, or L1210 when evaluated quantitatively.

(g) Of the 42 agents in this list which demonstrated "activity" by the criteria used herein, 39 percent were picked out by only one of the three-tumor systems used, and 24 percent were selected by all three tumor systems. Of those active against any one of the three systems, Sa180 missed the highest percentage, L1210 was next, and Ca755 missed the smallest percentage.

From these quantitative data, it would appear that the major sources of error in the present CCNSC primary screening operation probably stem from slightly too liberal criteria. This, we believe, is as it should be in primary screening, because it is not unusual for agents with borderline activity against one experimental tumor system (perhaps the one that picked them up) to show marked activity against another tumor system. More specifically, the major sources of error in the primary screens appear to be associated with:

(a) Preliminary acceptance of unrealistic so-called "maximum tolerated doses" from mortality data obtained in primary screening, where delayed mortality is not observed, is a much more important phenomenon than seems to be generally realized. The result will be the preliminary acceptance of a few agents which will provide a consistent T/C 0.40 or less only when an LD₅₀ or greater is employed.

(b) The use of the present host inanition criteria (<5 gms. host weight change difference and minimal therapeutic index); these criteria could result in passing over new classes of agents with real, but minimal, inhibitory activity and selection of others which are false positives by virtue of drug-induced host inanition.

Follow-up studies, i.e., toxicity determination with prolongea observation periods and specificity analyses, should help to overcome these deficiencies in primary screening.

The present results emphasize the importance and possible potential of broader spectrum screening.