Vitamin A and Carotenoids as Cancer Treatment Many research reports on the anti-cancer properties of vitamin A and the related retinoids have been published over the last 20 years. Most of these studies examined all-trans retinoic acid (RA). RA is formed in human tissues from beta-carotene and retinol, does not accumulate in the liver, thus it is not associated with significant hepatotoxicity.24 Treatment with RA is associated with many side effects, including headache, lethargy, anorexia, vomiting, and visual disturbance.24 Another retinoid used in cancer treatment is 13-Cis-retinoic acid (cRA), also known as isotretinoin.25 RA in vitro demonstrates growth inhibitory activity against at least 14 types of human cancers.24 Acute promyelocytic leukemia (APL) has been shown to respond well to RA, but not to cRA.26 In one study, nine of 11 patients with APL entered complete remission after treatment with 45 mg/m2 daily oral dose of RA.27 Similar results are reported elsewhere,28,29 and have been confirmed in vitro.30 Local application of an RA-containing cream demonstrated low toxicity and some histological improvement of cervical intraepithelial neoplasia II (CIN II) in a phase I study.31 In a phase III trial, RA led to complete regression of CIN II in 42 percent of women compared with 27 percent in the placebo group.32 No significant effect was noted in severe cervical dysplasia.32 After remission induced by conventional therapy, treatment with cRA is associated with fewer second primary tumors in head and neck squamous-cell carcinoma.33 Retinoic acid decreased the growth rate and increased differentiation of human small cell lung cancer lines in vitro.34 Daily oral administration of 300,000 IU vitamin A as retinol palmitate led to a significant reduction in second primary tumors and an increase in disease-free survival post-surgery in stage I lung cancer.35 However, a small trial of cRA at 200 mg/day found no appreciable benefit in the treatment of advanced non-small cell lung cancer. Of 23 patients evaluated in this trial, only one achieved a partial response to treatment.36 A trial of oral vitamin A at 100,000 IU/day in patients with resected malignant melanoma found no survival benefit compared with those taking placebo.37 In a trial of oral RA for hormone-refractory prostate cancer, dosed 45 mg/m2 daily, only a 15-percent response rate was seen.38 It is clear from these data that the effects of the retinoids as sole therapeutic agents are limited, perhaps mainly to hematologic malignancies, which tend to develop RA resistance over time.28 For further information on the use of retinoids in cancer therapy, refer to the review by MA Smith, et al.24 In contrast to the retinoids, comparatively little is known about the use of carotenoids as anti-cancer agents in vivo. The interest in carotenoids mainly stems from the extensive epidemiological evidence associating dietary intake with lower incidences of many cancer types.39 Alpha- and beta-carotene have been examined for in vitro tumor inhibitory activity against human neuroblastoma cell lines, and alpha-carotene was found to have 10 times the anti-tumor activity of beta-carotene.40 Currently there is some concern regarding supplementation with carotenoids,41 as beta-carotene has been associated with higher risk of lung cancer in smokers, but not in the general population.42 Aside from this concern, high doses of beta-carotene, even over long periods of time, are not associated with serious toxicity.39 There are also promising data showing chemopreventative activity of the carotenoid lycopene against prostate cancer.43 In vitro work suggests lycopene can induce differentiation, with vitamin D3, in human leukemia cells.44 One study showed lycopene to be a stronger inhibitor of human cancer cell proliferation in vitro than alpha- or beta-carotene.45 As yet, human trials are lacking on the use of lycopene. Vitamin A and Carotenoids with Radiation Evidence exists to support the use of retinoids concomitantly with radiotherapy. In vitro studies have shown retinoic acid (RA) causes radiosensitization in human tumor cell lines at concentrations which do not cause cellular toxicity. This effect was reversible with removal of RA.46 In mice bearing human breast adenocarcinoma tumor lines, the effect of local radiation was enhanced by supplemental vitamin A (150,000 IU) and beta-carotene (90 mg/kg) given during treatment. The beneficial effect of the supplemental treatment was noted as decreased tumor size and increased survival time. Supplemental vitamin A and beta-carotene plus radiation had significantly greater anti-tumor effect than radiation or supplementation alone. The effect of vitamin A was not significantly different from beta-carotene.9 In a randomized trial of oral vitamin A (1.5 million IU/day) plus radiotherapy for advanced cervical cancer, vitamin A plus radiotherapy significantly increased T-cell response and non-significantly reduced relapse rates compared with those undergoing radiotherapy only.46 A pilot human study of cis-retinoic acid (cRA) with radiotherapy and interferon-a2a on locally advanced cervical cancer noted a 47-percent tumor response and 33-percent complete remission rate, with no grade 3 or 4 toxicity noted. Historical controls without cRA treatment had a 42-percent tumor response rate and only 17-percent complete remissions.47 The ability of vitamin A to increase tumor response to radiation while reducing toxicity has been theorized to be due to the stimulation of immune response to tumor tissue.48 In a human study, beta-carotene at 75 mg daily during radiation treatment for advanced squamous cell carcinoma of the mouth significantly reduced the incidence of severe mucositis reactions without causing noticeable side effects. The remission rate was unchanged by beta-carotene treatment.49 In vitro evidence suggests synthetic beta-carotene does not have the radioprotective effect noted with the natural form.50 The meaning of this finding is as yet unclear. Vitamin A and Carotenoids with Chemotherapy Perhaps more than any other antioxidant treatment, retinoids are increasingly being pursued as adjunctive treatment to standard chemotherapeutics. Most evidence suggests an increased cytotoxic effect with reduced toxicity. In vitro studies using human small cell lung cancer lines demonstrated that incubation with retinoic acid (RA) led to an increased sensitivity to etoposide, but more resistance to doxorubicin.51 Human synovial sarcoma cells exposed to RA in vitro were found to have enhanced response to doxorubicin, vincristine, and especially cisplatin.52 Although the potential adverse interaction with doxorubicin was not confirmed in the latter study, this is an area that merits further definition. In studies of mice with transplanted human breast tumor tissue, concurrent treatment of either vitamin A or beta-carotene with cyclophosphamide led to a significantly greater tumor response and survival time compared to cyclophosphamide treatment alone. The effect of beta-carotene was roughly equivalent to that of vitamin A.9 Also in mice, co-administration of vitamin A with methotrexate ameliorated intestinal damage, without inhibiting its in vivo anti-tumor activity.53 In a phase I human trial of cisplatin with 13-cis-retinoic acid (cRA), the two agents were noted to have strong synergism against head and neck squamous cell carcinoma. Of 10 evaluable patients, all had complete tumor response at the primary site. Dosages of 20 mg/day cRA were well tolerated, but severe toxicities were seen at 40 mg/day.54 Extremely high oral doses of RA (150 mg/m2 daily) showed no inhibitory effect on the activity of cisplatin and etoposide on small cell lung carcinoma in humans. This dose also was not associated with any therapeutic benefit, and needed to be discontinued in a majority of patients due to side effects .55 Vitamin A palmitate at an oral dose of 50,000 IU twice daily, plus b-interferon and combined chemotherapy (epirubicin, mitomycin C, and 5-fluorouracil) prolonged symptom palliation in 35 percent of pancreatic cancer patients. This treatment was associated with severe toxicities in several systems, but only hepatotoxicity was thought to be associated with the addition of retinoids.56 Sequential treatment of non-lymphocytic leukemia patients with conventional chemotherapy, followed by 16,000 IU/day of retinol palmitate led to a further induction of maturation in blast cells than seen with chemotherapy alone. In three of four patients undergoing this sequential therapy, complete remission resulted.57 Addition of 400,000 IU/week vitamin A to a conventional chemotherapy regimen (doxorubicin, bleomycin, 5-fluorouracil, and methotrexate) led to improved survival with less than the expected severity of side effects compared with historical controls.10 Although the relative lack of toxicity compared to the retinoids makes it an attractive option, beta-carotene in combination with chemotherapy is a largely unexplored area. In mice, beta-carotene co-administration led to increased tumor growth delay with doxorubicin and etoposide, and increased tumor cell killing with cyclophosphamide in solid tumors. The co-administration of beta-carotene and 5-fluorouracil, however, reduced tumor growth delay in murine fibrosarcomas, but not in squamous cell carcinomas.58 Data on other carotenoids is lacking. Alternative Medicine Reviews, 1999;4(5):304-329 Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.