Panetta, speaking at the start of a weeklong trip to the Middle East and North Africa, did not offer any new steps the United States might take even as he renewed calls for a united international effort "to bring the Assad regime down."
Helicopter gunships opened fire over Aleppo on Sunday and the thud of artillery boomed across neighborhoods as government forces and rebels fought for control of the city, Reuters reports.
"If they continue this kind of tragic attack on their own people in Aleppo, I think it ultimately will be a nail in Assad's own coffin," Panetta said, speaking to reporters shortly before landing in Tunis.
"What Assad has been doing to his own people and what he continues to do to his own people makes clear that his regime is coming to an end. It's lost all legitimacy," he said, adding, "It's no longer a question of whether he's coming to an end, it's when."
Panetta mentioned the need to "provide assistance to the opposition," but did not appear to signal any new support.
The United States has said it is stepping up assistance to Syria's fractured opposition, although it remains limited to non-lethal supplies such as communications gear and medical equipment.
Reuters has learned that the White House has crafted a presidential directive, called a "finding," that would authorize greater covert assistance for the rebels, but stop short of arming them.
Panetta said he expected Syria to loom large in talks this week with leaders in Israel and Jordan, and flagged concerns about the security of Syria's chemical and biological weapons sites and the flow of Syrian refugees.
His trip began with a visit to Tunisia, which Washington has held up as a model for democratic change in the Middle East after a popular revolt forced autocratic leader Zine al-Abidine Ben Ali to flee the country on January 14, 2011, touching off a wave of political unrest across the Arab world.
The North African country has since calmly elected its own government, defying predictions it would descend into chaos, while Ben Ali's secret police has been disbanded and the news media enjoy unprecedented freedoms.
Still, Panetta said Tunisia had growing concerns about how to deal with the threat from al Qaeda and how to protect its borders.
NO ISRAELI DECISION ON IRAN
Panetta's visit to Israel later in the week is expected to include discussions on the threat from Iran's nuclear program, and will follow U.S. Republican presidential candidate Mitt Romney visit there on Sunday.
Earlier on Sunday, a senior aide to Romney said the candidate would respect an Israeli decision to use military force to stop Iran from developing a nuclear weapon. Romney himself balked at repeating that position when asked by CBS' "Face the Nation" program [ID:nL6E8IT0OY].
Panetta declined to comment on the Romney aide's remarks but appeared to suggest an Israeli attack was hardly a foregone conclusion.
"With regards to where Israel is right now, my view is that they have not made any decisions with regards to Iran and that they continue to support the international effort to bring pressure against Iran," Panetta said.
As Romney tries to portray U.S.-Israeli ties as strained, Panetta said there was unprecedented defense cooperation between the two countries.
"I'm proud of the defense partnership that we've built over the past several years. The U.S.-Israel defense relationship, I believe, is stronger today than it has been in the past," he said.
After visiting Tunisia, Panetta is expected to travel to Egypt to hold talks with newly elected Islamist President Mohamed Mursi and military chief Field Marshall Hussein Tantawi.
Panetta said he would urge the Egyptian government to complete the transition to full civilian rule and provide for as "broad a coalition as possible" within the government.
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