Let me try to answer your excellent question, and also to provide specifics that may help in any endeavor in this arena (and I compliment below the note of caution urged by Vinoth Jeevanesan and Krishan Khanduja writing above).

When engaged in integrative oncology, besides demanding a level of at least plausible evidence of efficacy (at least multiple cross-confirmative in vivo efficacy data or human clinical efficacy data), I demand any CAM (complementary and alternative medicine) demonstrate these types of safety:

Criteria for Herbal Safety

1. Clinical ("contextual") safety: the effects of contrary actions in some specific disease contexts (below)

2. Toxicity: this is intrinsic toxicity and includes hepatotoxicity and renaltoxicity for example (see examples below)

3. Co-toxicity: containing contamination with adverse co-ingredients (see below)

4. Pharmacokinetic safety: adverse drug interactions over the cytochrome p450 hepatic enzyme system of CYP metabolism when an herbal and a drug share a particular CYP metabolic mediation.

1. Clinical ("contextual") Safety

An example would be using Astragulus, found in many herbals especially for women, and extensively used in TCM (Traditional Chinese Medicine). In breast cancer patients for example the potential problem is the disturbing findings of Lynn James (with USDA) that this herb exhibits estrogenic properties (Can J Comp Med, 1972), and hence could stimulate estrogen-driven carcinogenesis and tumorigenesis.

2. Intrinsic Toxicity

Many herbals are intrinsically toxic due to their own components. So, in a review on herbs and the dialysis patient, Naomi Dahl at UMDNJ–Robert Wood Johnson Medical School (Semin. Dial, 2001) suggested the avoidance of borage (Borago officinalis), comfrey (Symphytum spp.), coltsfoot (Tussilago farfara), and liferoot (Senecio aureus) because of their pyrrolizidine alkaloid content and hence hepatotoxic potential, and sassafras (Sassafras albidum) because of its safrole content. Further recommendations by the same group included the avoidance of chaparral (Larrea tridentata) and germander (Teucrium chamaedrys) also, because of their potential hepatotoxic effects.

And comfrey via its constituent pyrrolizidine alkaloids not only produces hepatotoxicity in livestock, but also in humans, as well as being mutagenic in the liver, and inducing carcinogenicity in experimental animals, yet it is still widely available despite an FDA Advisory against its use.

3. Co-toxicity via Contamination

Contamination is a not uncommon problem with herbals. Richard Ko reported the analysis of 260 products collected from Californian retail herbal stores, finding that 32% contained undeclared pharmaceuticals (chlorpheniramine, methyltestosterone, phenacetin, and ephedrine) or heavy metals (lead, arsenic, and mercury), with 23 having more than one adulterant (N. Engl. J. Med, 1998). This sorry state of affairs has been further confirmed recently by Jun-hua Zhang and colleagues in China who detailed how the complexity and non-uniformity of the ingredients in herbal medicines engenders contamination (e.g. with toxic metals, pesticides residues, and microbes), adulteration and misidentification (Complement Ther Med, 2012).

A dramatic reminder of compound toxicity occurred in early 1992: cases of renal failure, rapidly progressing to end-stage renal disease (ESRD) were reported in Belgium, which were associated with daily intake of slimming pills containing root extracts from Chinese herbs (Stephania tetrandra and Magnolia officinalis). Suspected was the inadvertent replacement of Stephania tetrandra by Aristolochia fangchi. This is common since TCM classifies S. tetrandra (Pin Yin name: Han Fang Ji) and A. fangchi (Pin Yin name: Guang Fang Ji) within the same therapeutic ‘Fang Ji’ family, and herbal ingredients are traded using this common Pin Yin name, confirmed in the data provided by Jean-Louis Vanherweghem's team in Brussels which documented aristolochic acid nephropathy (AAN), a progressive renal interstitial fibrosis frequently associated with urothelial malignancies.

Aristolochia plants are used extensively in herbal preparations in China, Taiwan and Hong Kong, from where AAN is now being increasingly reported, with a similar disease pattern described in Europe (Germany, UK, France, Spain), Asia (Japan, Korea) and the USA.

Yet despite the Food and Drug Administration's warnings concerning the safety of botanical remedies containing aristolochic acid, these herbs are still sold via the Internet and in many herbal stores.

4. Pharmacokinetic Safety

A classic example here is St. John's Wort (SJW). St. John's Wort (SJW) decreases the bioavailability of CYP and P-gp substrates, but more more critically, due to the fact that its metabolism is mediated by the liver enzyme CYP3A4 which metabolically mediates over 4000 traditional drugs including cancer agents, it reversed the cytotoxicity of paclitaxel (Taxol). There is also robust data of adverse interaction with certain anti-anxiety drugs (benzodiazepines), antidepressants, oral contraceptives, cardiovascular agents (digoxin), statins, as well as several anticancer drugs such as irinotecan Camptosar), imatinib (Gleevec) and the taxanes docetaxel (Taxotere) and paclitaxel (Taxol), among many others, as documented by Francesca Borrelli and Angelo Izzo at the University of Naples (AAPS J, 2009; see also Japanese researchers Atsushi Wada and colleagues (Drug Metab Pharmacokinet 2002)).

This problematic interaction with taxanes is also, my research shows, shared with resveratrol: a recent preclinical study of resveratrol from Masuyuki Fukui and colleagues at the University of Kansas found that that resveratrol strongly reduces the susceptibility and efficacy of certain breast cancer cells (including triple negative MDA-MB-231 cells) to paclitaxel-induced cell death / apoptosis in culture and also in vivo in mice (not observed in non-TNBC MCF-7 cells), and although this has not been demonstrated in the human clinical setting, it suggests caution in co-administration of resveratrol and paclitaxel (Taxol) (and possibly by extrapolation with other taxanes, although these were not studied) [Fukui et al., Eur J Cancer 2010).

And although the data as to SJW and oral contraceptives is not yet decisive, nonetheless it would be prudent to advise women using SJW that oral contraceptives may not afford sufficient protection; indeed, unexpected pregnancies were reported in some women who consumed SJW while taking oral contraceptives (Vlachojannis et al., Pharmacol Res 2011).

Summary

For me, working in integrative oncology, inclusion of an agent into an integrative regimen follows ten broad inclusion/eligibility requirements (and many exacting methodological and strength-of-evidence sub-requirements). Briefly, the components of the regimen are

(1) must be selected through a process of strict evidence-based review and critical appraisal;

(2) must exhibit multiple cross-confirmatory data of:

(3) efficacy,

(4) safety and

(5) absence of clinically significant adverse pharmacokinetic interactions, intrinsic toxicity, co-toxicity, or clinical / contextual safety concerns as to their anticancer activity in both:

(6) chemopreventive and therapeutic contexts, and

(7) at the in vivo level or higher (human clinical trials), and

(8) must affect positively multiple molecular pathways known to be active in carcinogenesis, tumorigenesis, malignant transformation and metastatic development and migration, and related malignant processes, and

(9) with minimal potential for MDR (multi-drug resistance), or evidence of anti-MDR, activity, and finally (10) with non-interfering complimentary, additive or synergistic activity in concurrent administration with each other.

The Promise of Integrative Oncology

This however, despite exceedingly stringent requirements, leaves open the potential for many CAM interventions as both safe and effective in oncology, such as for example the pituitary hormone melatonin, the omega-3 fatty acid DHA, vitamin D3, among others.

It should therefore be clear that one cannot assume the safety of herbal and CAM interventions in oncology but by applying the demands to demonstrate the four types of safety I detailed above, this can assure the lack of harm, and then this should be followed by the hard work of establishing through evidence-based systematic review and critical appraisal the therapeutic efficacy of any agent being considered in the oncology context.

Constantine Kaniklidis

Director of Medical research, No Surrender Breast Cancer Foundation (NSBCF)

European Association for Cancer research (EACR)

Thanks Yousefzadeh Mam. Please provide me ur email id. I want to talk further.

No doubt there is a plenty of literature in favor of cancer chemopreventive activity of non-nutritional plant products in animal experiments. But one should not ignore the other side of the coin. Some reports on adverse effects of plant polyphenols on male reproductive system have appeared recently in the literature. So till the controversy is not resolved completely, one should not recommend their use for chemopreventive /chemotherapeutic purposes.

Let me try to answer your excellent question, and also to provide specifics that may help in any endeavor in this arena (and I compliment below the note of caution urged by Vinoth Jeevanesan and Krishan Khanduja writing above).

When engaged in integrative oncology, besides demanding a level of at least plausible evidence of efficacy (at least multiple cross-confirmative in vivo efficacy data or human clinical efficacy data), I demand any CAM (complementary and alternative medicine) demonstrate these types of safety:

Criteria for Herbal Safety

1. Clinical ("contextual") safety: the effects of contrary actions in some specific disease contexts (below)

2. Toxicity: this is intrinsic toxicity and includes hepatotoxicity and renaltoxicity for example (see examples below)

3. Co-toxicity: containing contamination with adverse co-ingredients (see below)

4. Pharmacokinetic safety: adverse drug interactions over the cytochrome p450 hepatic enzyme system of CYP metabolism when an herbal and a drug share a particular CYP metabolic mediation.

1. Clinical ("contextual") Safety

An example would be using Astragulus, found in many herbals especially for women, and extensively used in TCM (Traditional Chinese Medicine). In breast cancer patients for example the potential problem is the disturbing findings of Lynn James (with USDA) that this herb exhibits estrogenic properties (Can J Comp Med, 1972), and hence could stimulate estrogen-driven carcinogenesis and tumorigenesis.

2. Intrinsic Toxicity

Many herbals are intrinsically toxic due to their own components. So, in a review on herbs and the dialysis patient, Naomi Dahl at UMDNJ–Robert Wood Johnson Medical School (Semin. Dial, 2001) suggested the avoidance of borage (Borago officinalis), comfrey (Symphytum spp.), coltsfoot (Tussilago farfara), and liferoot (Senecio aureus) because of their pyrrolizidine alkaloid content and hence hepatotoxic potential, and sassafras (Sassafras albidum) because of its safrole content. Further recommendations by the same group included the avoidance of chaparral (Larrea tridentata) and germander (Teucrium chamaedrys) also, because of their potential hepatotoxic effects.

And comfrey via its constituent pyrrolizidine alkaloids not only produces hepatotoxicity in livestock, but also in humans, as well as being mutagenic in the liver, and inducing carcinogenicity in experimental animals, yet it is still widely available despite an FDA Advisory against its use.

3. Co-toxicity via Contamination

Contamination is a not uncommon problem with herbals. Richard Ko reported the analysis of 260 products collected from Californian retail herbal stores, finding that 32% contained undeclared pharmaceuticals (chlorpheniramine, methyltestosterone, phenacetin, and ephedrine) or heavy metals (lead, arsenic, and mercury), with 23 having more than one adulterant (N. Engl. J. Med, 1998). This sorry state of affairs has been further confirmed recently by Jun-hua Zhang and colleagues in China who detailed how the complexity and non-uniformity of the ingredients in herbal medicines engenders contamination (e.g. with toxic metals, pesticides residues, and microbes), adulteration and misidentification (Complement Ther Med, 2012).

A dramatic reminder of compound toxicity occurred in early 1992: cases of renal failure, rapidly progressing to end-stage renal disease (ESRD) were reported in Belgium, which were associated with daily intake of slimming pills containing root extracts from Chinese herbs (Stephania tetrandra and Magnolia officinalis). Suspected was the inadvertent replacement of Stephania tetrandra by Aristolochia fangchi. This is common since TCM classifies S. tetrandra (Pin Yin name: Han Fang Ji) and A. fangchi (Pin Yin name: Guang Fang Ji) within the same therapeutic ‘Fang Ji’ family, and herbal ingredients are traded using this common Pin Yin name, confirmed in the data provided by Jean-Louis Vanherweghem's team in Brussels which documented aristolochic acid nephropathy (AAN), a progressive renal interstitial fibrosis frequently associated with urothelial malignancies.

Aristolochia plants are used extensively in herbal preparations in China, Taiwan and Hong Kong, from where AAN is now being increasingly reported, with a similar disease pattern described in Europe (Germany, UK, France, Spain), Asia (Japan, Korea) and the USA.

Yet despite the Food and Drug Administration's warnings concerning the safety of botanical remedies containing aristolochic acid, these herbs are still sold via the Internet and in many herbal stores.

4. Pharmacokinetic Safety

A classic example here is St. John's Wort (SJW). St. John's Wort (SJW) decreases the bioavailability of CYP and P-gp substrates, but more more critically, due to the fact that its metabolism is mediated by the liver enzyme CYP3A4 which metabolically mediates over 4000 traditional drugs including cancer agents, it reversed the cytotoxicity of paclitaxel (Taxol). There is also robust data of adverse interaction with certain anti-anxiety drugs (benzodiazepines), antidepressants, oral contraceptives, cardiovascular agents (digoxin), statins, as well as several anticancer drugs such as irinotecan Camptosar), imatinib (Gleevec) and the taxanes docetaxel (Taxotere) and paclitaxel (Taxol), among many others, as documented by Francesca Borrelli and Angelo Izzo at the University of Naples (AAPS J, 2009; see also Japanese researchers Atsushi Wada and colleagues (Drug Metab Pharmacokinet 2002)).

This problematic interaction with taxanes is also, my research shows, shared with resveratrol: a recent preclinical study of resveratrol from Masuyuki Fukui and colleagues at the University of Kansas found that that resveratrol strongly reduces the susceptibility and efficacy of certain breast cancer cells (including triple negative MDA-MB-231 cells) to paclitaxel-induced cell death / apoptosis in culture and also in vivo in mice (not observed in non-TNBC MCF-7 cells), and although this has not been demonstrated in the human clinical setting, it suggests caution in co-administration of resveratrol and paclitaxel (Taxol) (and possibly by extrapolation with other taxanes, although these were not studied) [Fukui et al., Eur J Cancer 2010).

And although the data as to SJW and oral contraceptives is not yet decisive, nonetheless it would be prudent to advise women using SJW that oral contraceptives may not afford sufficient protection; indeed, unexpected pregnancies were reported in some women who consumed SJW while taking oral contraceptives (Vlachojannis et al., Pharmacol Res 2011).

Summary

For me, working in integrative oncology, inclusion of an agent into an integrative regimen follows ten broad inclusion/eligibility requirements (and many exacting methodological and strength-of-evidence sub-requirements). Briefly, the components of the regimen are

(1) must be selected through a process of strict evidence-based review and critical appraisal;

(2) must exhibit multiple cross-confirmatory data of:

(3) efficacy,

(4) safety and

(5) absence of clinically significant adverse pharmacokinetic interactions, intrinsic toxicity, co-toxicity, or clinical / contextual safety concerns as to their anticancer activity in both:

(6) chemopreventive and therapeutic contexts, and

(7) at the in vivo level or higher (human clinical trials), and

(8) must affect positively multiple molecular pathways known to be active in carcinogenesis, tumorigenesis, malignant transformation and metastatic development and migration, and related malignant processes, and

(9) with minimal potential for MDR (multi-drug resistance), or evidence of anti-MDR, activity, and finally (10) with non-interfering complimentary, additive or synergistic activity in concurrent administration with each other.

The Promise of Integrative Oncology

This however, despite exceedingly stringent requirements, leaves open the potential for many CAM interventions as both safe and effective in oncology, such as for example the pituitary hormone melatonin, the omega-3 fatty acid DHA, vitamin D3, among others.

It should therefore be clear that one cannot assume the safety of herbal and CAM interventions in oncology but by applying the demands to demonstrate the four types of safety I detailed above, this can assure the lack of harm, and then this should be followed by the hard work of establishing through evidence-based systematic review and critical appraisal the therapeutic efficacy of any agent being considered in the oncology context.

Constantine Kaniklidis

Director of Medical research, No Surrender Breast Cancer Foundation (NSBCF)

European Association for Cancer research (EACR)

Thank you so much Kaniklidis Sir for providing a highly satisfactory and valuable information. Actually I am working on some toxic plants and checking their anticancer and antioxidant activities. Thanks Sir.

The premise of the question is not correct. Cancer is not one disease and no cancer type has been shown to be a degenerative disease.

Uckun Sir I know cancer is not a single diseases and there are more than hundred different kinds of cancer which effects human beings. My question is different. I would like to know is this is fare and safe to use toxic plants after isolation in daily routine to avoid some severe cancers. As we use different dietary medicinal plants and drugs in a daily routine like amla, trifla, satavari, and so on to increase immunity power and to prevent various diseases caused by environmental factors.

These points are all valuable, and raise many shrewd points. I will offer several additional points here to further enhance the discussion. First, it is important to remember that there is more to natural / herbal agent - and CAM intervention in general - safety (or harm) than just toxicity (or cytotoxicity if the agent / intervention exhibits, as many do, preferential targeting of malignant over normal cells).

So for example a natural agent may:

(1) lack demonstrable (i.e., intrinsic) toxicity but exhibit adverse context-dependent pharmacokinetics (resveratrol with paclitaxel and nab-paclitaxel for instance) or

(2) be problematic in terms of contextual safety (a potentially estrogenic herb like Astragulus in patients at elevated risk of breast cancer, or in breast cancer patients with active HR-positive disease, or powerful CYP3A4 inhibitors like St. John's Wort or garlic concurrent with HIV retrovirals / protease inhibitors, supported by human clinical data), or

(3) like curcumin, exhibit adverse interaction under isolated and bounded concurrent use with the taxane paclitaxel or the alkylating agent cyclophosphamide where preclinical data suggest potential interference with the pro-apoptotic activity of these chemotherapies (and although these findings are under intense challenge by other researchers - myself included, and especially - nonetheless professional and ethical imperatives in these specialized concurrency scenarios suggests suitable and exceptional caution).

Second, we can be only provisionally and partially reassured of the safety of natural agents by their widespread use in human food consumption, but cannot take this as a dispositive test: comfrey has been in use for decades (and in some cultures, above a century) both as a tea and as a food ingredient, yet it exhibits problematic hepatotoxicity and renaltoxicity sufficient to have engendered an FDA Advisory against both use and continued sale (and nonetheless remains easily accessible). And numerous components of plant native to or widespread use in the Middle East have either significant toxicities or adverse pharmacokinetics or may be estrogenic (with only some of these detrimental effects countervailed by beneficial components in other parts of the diet).

Third, it must be remembered - and William Jackson's caution here is particularly well taken - that natural agents are full-fledged pharmacological agents and can hence exhibit the full spectrum of modulation of pathogenic, carcinogenic and tumorigenic processes and molecular pathways that any oncotherapeutic (endocrine, chemotherapeutic, or biological) agent exhibits; these are not "weak (or necessarily always benign) sisters". For example, curcuminoids have demonstrable activity in multiple cell signaling and molecular pathways1: cyclin D1 and cyclin E, c-myc, p21, p27, p53, HER-2, EGFR, AP-1, Bcl-2, Bcl-xL, Bax, cIAP1, xIAP, cFLIP, survivin, MMP-2/9 and adhesion molecules, VEGF, VEGFR1, IGF-1R, CXCR-4, NF-kB, TNF, IL-6, IL-1, STAT3/5, JNK, COX-2, 5-LOX, iNOS, Wnt/β-catenin, caspase activation pathways (caspase-8, 3, 9), death receptor pathways (DR4, DR5), mitochondrial pathways, protein kinase pathway (JNK, PI3K/Akt, ERK, AMPK), and both HDAC/DNMT inhibitory activity, and significant anti-metastatic activity at all stages of the metastatic cascade, among dozens more.) Therefore natural agents should not be viewed within the limited perspective of solely immunomodulatory agents, or anti-inflammatory-process agents, or antioxidants; this may - and appears to be - be only a small part of their overall anticancer activities which certainly include direct tumoricidal, anti-proliferative, anti-invasive, anti-adhesive, anti-migrative, anti-colonizing, anti-angiogenic, pro-apoptotic, and a host of epigenetic, activities among numerous other antitumor effects, and - as pointed out by William Jackson above - as adjunct oncotherapeutic agents for the amelioration, or enhancement, of primary therapeutic or adverse effects from traditional medicine, or like ginger, as aids in supportive oncology (RCT data confirming benefit in CINV).

Finally, I would encourage Pracheta in her current research endeavor: amla; the myrobalans of trifla (triphala in the medical literature); and satavar (med., shatavari) all have promising preclinical evidence of multiple anticancer activities as well as chemoprotective and hepatoprotective properties (although some may exhibit CYP3A4 metabolic mediation), in addition to benefits in several cardiovascular, gastrointestinal, dermatologic, endocrinological, and degenerative diseases, with research support from NCCAM (National Center for Complimentary and Alternative Medicine, under the National Institute of Health (NIH)), and despite uninformed claims to the contrary, we have human clinical double-blind, placebo-controlled trials suggesting efficacy for uses of some Ayurvedic herbs outside the oncology context. Besides safety issues along the protocol lines I suggested above, products from online sources are not uncommonly (21%) contaminated with lead (most common), mercury, or arsenic. However, it must be born in mind that this level of contamination, although of no small concern, it should be kept in perspective that this is not massively different from similar contamination found regularly in quality assurance testing of non-Ayurvedic natural agents (quality control of herbals is unnecessarily poor, often shockingly so, for this day and age!).

Constantine Kaniklidis

Director of Medical research, No Surrender Breast Cancer Foundation (NSBCF)

European Association for Cancer research (EACR)

As they say, "what doesn't kill you will strengthen you". While this applies to pharmacology, it has been one of the central tenets of homeopathy and a marriage of its best practice with the search for hormesis may be a justification for the use of non-dietary plants. Often much to the ire of big pharma:

http://www.ncbi.nlm.nih.gov/pubmed/20558608