By David N. Leff

In the last few years, "apoptosis" has become a buzzword, describing what happens to cells that decide to commit suicide by programmed death.

At the human level, "assisted suicide" is a very trendy expression, signifying the choice of individuals with unbearable disease to obtain professional help in ending their lives.

The term "mass slow suicide" might well be applied to large populations of people in advanced Western countries who die of lung or colorectal cancer.

Epidemiological studies strongly support the notion that cigarette smoking has made pulmonary carcinoma the No. 1 cause of cancer death in the U.S., with imprudent diet putting colorectal cancer in second place.

"Lung cancer," reports the National Cancer Institute's (NCI) latest statistical survey, Rates and Risks, "accounts for 39 percent of all cancer deaths — 35 percent in males and 21 percent in females." It adds: "Cigarette smoking is the major cause of lung cancer."

Colorectal cancer comes in second in the U.S. population, the NCI figures state, "with an estimated 56,000 deaths in 1994." The study indicts dietary fat intake, red meat consumption and alcohol ingestion among the principal promoters of colon and rectum malignancy.

In a typical year, physicians diagnose some 150,000 new cases of colorectal cancer. Their front-line chemotherapy drug against this menace is the antimetabolite 5-fluorouracil (5FU). It has a very narrow window of limited efficacy between too-low, hence useless, doses and too-high doses with horrendous side-effect toxicity to patients.

This compound of first and last resort is effective (but usually transiently) in only about 20 percent of advanced colorectal cancers (CRC), pointed out clinical oncologist and cell biologist Robert Coffey, at Vanderbilt University Medical Center, in Nashville. "The remaining 80 percent," he told BioWorld Today, "do not benefit from chemotherapy because CRC tumors harbor a disabled p53 tumor suppressor gene."

Intact p53 responds to DNA damage by arresting cell division and inducing apoptosis in tumor cells, while sparing normal ones. In that programmed cell death, the actual executioners are oxygen free radicals, the highly cytotoxic unpaired electrons of the elemental O₂ molecule.

In those few CRC tumors with functioning p53, 5FU chemotherapy increases the level of that tumor suppressor, which then induces a gene for p21. A powerful blocker of the cell cycle, p21 apparently has antitumor effects independent of p53, but involving antioxidant chemicals that counterattack those DNA-damaging oxygen free radicals.

Beefing Up Veggies, Vitamins

The best known of these antioxidants are vegetables and vitamins, particularly C, E and ß-carotene. which reportedly help prevent CRC in particular. Given the few and modest victories in the quarter-century-old "War on Cancer," voices are heard increasingly these days to soft-pedal chemotherapy and go for such antioxidants, which are widely available over the counters of health food stores.

"Traditionally," Vanderbilt's Coffey pointed out, "antioxidants like vitamin E and beta-carotene have been touted as agents that prevent cancers from forming. While a chemopreventive effect has not yet been proven, we have found intriguing evidence that antioxidants may help treat established cancers."

Coffey's approach was to throw antioxidants into the fray, to jazz up the power of anticancer drugs, specifically 5FU, the main CRC chemotherapeutic.

Nature Medicine for November carries the report of his group's initial mouse and test-tube experiments. Its title: "Antioxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: A p53-independent induction of p21 via C/EBPß."

Their in vivo strategy was to treat mice carrying human CRC tumors with an experimental combination chemotherapy: 5FU plus two antioxidants, one a synthetic chemical, PDTC (pyrrolidinedithiocarbamate), which has been tried in AIDS therapy; the other, a vitamin E analogue.

Defeating Tumor Resistance To 5FU

The team's rationale was based on evidence that antioxidants, besides preventing gene mutations, can directly induce apoptosis in tumor cells. So they expected their antioxidant cocktail to downgrade the resistance of those malignant cells to 5FU chemotherapy.

Coffey and his co-authors began by injecting nude mice with human CRC tumor-cell xenografts. When these had grown into tumors of 155-cubic-millimeter volume, they gave some animals weekly shots of the vitamin E or PDTC antioxidant, plus 5FU. Other cohorts received the three ingredients singly. Control rodents got saline solution.

After four weeks, the tumors on those controls had grown so large that the mice had to be sacrificed. None of the animals dosed with single agents enjoyed a halt in tumor growth, but the PDTC+5FU combo cohort experienced complete tumor regression, which, Coffey said, "has persisted for over four and one-half months, with no evidence of tumor recurrence."

"While results in the lab and in animal models are very encouraging," Coffey observed, "clinical trials are necessary to determine whether the combination of antioxidants and chemotherapy will be as effective in humans."

He plans to begin "a Phase II trial of 5FU plus vitamin E at Vanderbilt within a month," adding, "We would also like to embark on a PDTC-5FU study, but there is additional work we need to do in the animal, in terms of optimizing the dose of the dithiocarbamate, before we're ready to embark on a clinical trial."

He explained that no Phase I trial is required "because vitamin E is already being used in the clinic. We would probably go to fairly high doses of vitamin E, in conjunction with 5FU, in patients with advanced colorectal cancer. We would anticipate having 20 to 30 patients in that study."

Coffey concluded: "An added benefit of this combination appears likely, in that these antioxidants protect rapidly dividing normal tissues, such as the gut, from the injurious side effects of chemotherapy." *