In the third preseason game of the 1999 preseason, the St. Louis Rams lost starting QB Trent Green to a season-ending ACL injury as San Diego Chargers S Rodney Harrison hit him from behind in what many perceived to be a dirty play. Fifteen years later, Rams QB Sam Bradford went down in that fateful third preseason game against the Cleveland Browns re-injuring his ACL.
The perils of playing your key starters in what are essentially engaged practice sessions have always been apparent, and the two instances are certainly remembered well (as in starkly not fondly) as evidence thereof.