that the energy requirements for certain neurons in the brain are higher than those of other somatic cells and, perhaps, may be as high as those of cancer cells. If the annonaceous acetogenins are to be useful systemically against cancerous cells, their therapeutic indexes must be favorable. The data currently available are limited, but still some comparisons can be presented. The work cited above using iv infusions of annonacin (3) in rats125 showed neurotoxic effects at 3.8 and 7.6 mg/kg/day for 28 days. In the 3PS assay using mice, 3 was active (124% T/C) at 0.95 mg/kg/day for 10 days.29 Thus, disregarding the difference in species, the therapeutic index for 3 would be between 4 and 8. Asimicin (1) in the murine 3PS assay was active (124% T/C) at 0.025 mg/kg/day for 10 days but toxic at 0.22 mg/kg/day.29 Accordingly, the therapeutic index for 1 in mice is about 10. These numbers are tolerable for anticancer agents, although, especially for long-term therapy, it might be wise to monitor the patient for adverse neurological effects. The observation that the neurologic symptoms improve and stabilize after stopping daily consumption113 suggests that the condition need not be life-threatening. Given the choice between dying of cancer and experiencing some symptoms of Parkinsonism after years of effective treatment with acetogenins, most cancer patients would choose the latter.

In 1999, I took an early retirement from Purdue University and was hired as Vice President for Research and Development and Chief Scientific Officer at Nature’s Sunshine Products (NSP) in Spanish Fork, UT. This position gave me the unique opportunity to develop some useful commercial products containing the annonaceous acetogenins. Paw paw (Asimina triloba) was selected as the best source of biomass because it is abundant in the eastern United States and its collection and commercial development would not be encumbered by having to interact with customs officials, listen to claims of “biopiracy”, and deal with potential embargos, as can be encountered when importing botanicals. The utility of the acetogenin-containing extracts in pest control seemed to be a good, practical, application.71 Market analysis revealed that some 16 million people annually (primarily school children) in the United States are infested with pyrethrin-resistant head lice, and a new head lice shampoo that circumvented pesticide resistance101 might gain success as an innovative health-care product.

It took two years to secure sources of supply of the paw paw twigs (collected in May), contract for and secure large-scale extraction, standardize the extract (using brine shrimp and HPLC/MS/MS), formulate the best shampoo base, select synergistic additives (thymol and tea tree oil), and ensure stability. In vitro tests with head lice were performed to determine the optimum concentration, treatment time, and dosing schedule. The final product passed the Draize test in rabbits for eye irritation,132 and the product, named Paw Paw Lice Remover Shampoo, was subjected to a clinical trial in school children, some of whom had harbored head lice for up to three years while unsuccessfully using the ineffective pyrethrin-based products that are on the market. The school nurses involved were happy to report that the paw paw shampoo was 100% effective, and we published a clinical report describing the product and the trial results.133 The product was introduced in 2001. Subsequently, we worked with Carroll-Loye Biological Research (Davis, CA) to demonstrate that the shampoo is 100% effective at killing fleas in vitro134 and on dogs.135 The shampoo was also effective at killing ticks in vitro.136 Unfortunately, the product was discontinued after encountering insufficient sales.

In the early 1990s, biological testing at Merck and Company had determined that a series of our acetogenins was active against the parasite Hemonchus contortus, a nematode that infects sheep, goats, and other animals. Earlier tests at Eli Lilly and Company (Greenfield, IN) had shown the effectiveness of our acetogenins and paw paw extracts against Caenorhabditis elegans, a free-living nematode.[17,19] Consequently, we added a capsule containing 12.5 mg of standardized paw paw extract to an established NSP combination product called Paraclease. Three additional new potential paw paw products were prepared in the NSP Pilot Plant Laboratory under my direction. These include a paw paw ointment (that controls skin cancers, herpes simplex, herpes zoster, athletes foot, the pain of bee stings, etc.), a paw paw lotion (that controls acne, skin infections, etc.), and a paw paw spray (that controls most plant pests). At Purdue we had shown, using flat head minnows, that paw paw extracts are very potent as natural piscicidal agents and would be much less expensive than rotenone. Unfortunately, the high costs involved in obtaining EPA registrations and FDA approvals for these new pest control and drug uses will probably prevent these products from being sold in the United States.

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mg of standardized paw paw extract to an established NSP combination product called Paracleanse. Three additional new potential paw paw products were prepared in the NSP Pilot Plant Laboratory under my direction. These include a paw paw ointment (that controls skin cancers, herpes simplex, herpes zoster, athletes foot, the pain of bee stings, etc.), a paw paw lotion (that controls acne, skin infections, etc.), and a paw paw spray (that controls most plant pests). At Purdue we had shown, using flat head minnows, that paw paw extracts are very potent as natural piscicidal agents and would be much less expensive than rotenone. Unfortunately, the high costs involved in obtaining EPA registrations and FDA approvals for these new pest control and drug uses will probably prevent these products from being sold in the United States.

After determining that the standardized paw paw extract was apparently safe acutely due to emesis upon overdosage, we prepared it for oral administration in capsular form (12.5 mg/capsule to be administered qid) for human testing. The centuries-old tradition of human consumption as an edible fruit, the fact that the fruits contain appreciable levels of the acetogenins and are, apparently, eaten with impunity, the previous marketing by Eli Lilly and Company of the extract as an emetic, and the lack of any adverse reports about paw paw at the FDA provided compelling evidence that this plant has a historical record of being generally recognized as being safe. FDA consultants assured us that, for development as a dietary supplement, testing in human subjects could proceed. A law in Nevada permits terminal cancer patients, under the direction of their physician, to try new treatments. James Forsythe, M.D., Director of the Cancer Screening and Treatment Center of Nevada, in Reno, agreed to recruit test subjects for us among his stage 4 cancer patients.

Dr. Forsythe found that the paw paw capsules, named Paw Paw Cell-Reg, when given one capsule qid, stabilized a number of patients with advanced breast, lung, prostate, lymphatic, and colorectal cancers as well as with Waldenstrom’s macroglobulemia; furthermore, the patients showed no abnormalities in liver, kidney, electrolyte, blood sugar, or bone marrow functions.[137] The product was effective whether used alone or as an adjuvant with other treatments including IGF-I and insulin-potentiation. Evidence of effectiveness included reductions in the blood levels of tumor antigens, measurable decreases in tumor sizes, inhibition of further metastases, weight gain, increased mobility, enhanced energy, and increased duration of survival. We expanded the number of case studies, with similar encouraging results, and introduced the product to the market, as a dietary supplement, in the spring of 2003. The small number (26) of adverse events reported, through March 2008, and the success of the product suggest that the inhibition of cellular energy (ATP) with the mixture of annonaceous acetogenins from paw paw offers a novel, safe, and effective mechanism for the alleviation of cancer. As a dietary supplement, however, the paw paw product cannot be advertised as a treatment in the United States, and the company (NSP) makes no such claims for the product. A U.S. patent, assigned to NSP, is pending[138] and protects the extract and its antitumor use in animals and humans.

Acknowledgment. This work is dedicated to the memory of my sister, Janean A. (McLaughlin) Kistel, whose courageous battle with breast cancer inspired me to never give up in the search for a cure. Financial support is acknowledged from Nature’s Sunshine Products, Spanish Fork, UT; R01 Grant No. 30909, from NCI, NIH; the Purdue Cancer Research Center; the Trask Fund from the Purdue Research Foundation; and Marilyn Cochran, San Angelo, TX (in memory of Shiela). Thanks are due to all of the students, postdoctoral fellows, technicians, visiting scholars, and colleagues who each devoted a part of their working life to the various acetogenin projects. Special thanks go to John F. Kozlowski for his help in the preparation of the manuscript.

(1) American Cancer Society. Cancer Facts and Figures 2007; American Cancer Society: Atlanta, 2007.