Mandatory locking can stop other processes reading/writing the file even if it does not lock it. However, it is system dependent. See fcntl(2) and linux/Documentation/mandatory.txt if you're on linux. (Update: read the section on Leases in fcntl(2) too, it might be what you want.)

Note that if you want to lock mailbox files, there's some special convention to lock them through a lockfile, but I don't know the details.

Also, you might not even need locking. In some cases, you can just write the modifications to a different file and rename/link the new file to the old name, thus replacing the old file atomically.

Update: good as it sounds, even mandatory locking or leashes may not be enough if the programs not controlled by you want to write the file asynchronously. If they do not do the writing in an atomic manner, your script may lock the file in an invalid state, when it is only paritally changed. This is why co-operative locking is important.