Dr. Bill Hrushesky "Successful Cancer Therapy Development: Beating the Odds by Respecting Human Circadian Organization"
Director, Research Service Line
VA Research and Development
Columbia, South Carolina
Dr. David Blask "Melatonin: An Integrative Chronobiotic Anticancer Therapy Whose Time Has Come"
Bassett Research Institute
Cooperstown, NY
Dr. Paolo Lissoni "Clinical Experience with Melatonin Alone or Combined with the Standard Anticancer Therapies in Medical Oncology"
Division of Radiation Oncology, San Gerardo Hospital
Milan, Italy
Hrushesky
Founded Medical Chronotherapeutics
Circadian rhythm can be tracked via wristband
Rise in rate and BP before rising as indicator of circadian rhythm
There is a universal pain cycle, presumed circadian
Radiation is targeted to G2 part of cell cycle, most prominent in afternoon Ovarian trial found best schedule of Dox in morning, Cisplatinum in evening
5 yr 44% survival in optimal schedule vs 11% when timing was reversed
Colorectal cancer trial
Circadian oriented delivery of 5FU (S phase agent) in evening/overnight best, allows increased dose.
Renal cancer treatment greatly optimized by circadian delivery
Hepatic arterial efficacy increased with chronotherapy Lissoni
02:28:32 melatonin for neuron dosages w/Il-2 , it produces Il-12
Other pineal gland hormones help too and are amplified by melatonin 02:35:00
Naltrexone beneficial
Low dose Il-2 helpful
IL-12 + Il-2 melatonin and total pineal replacement therapy 02:37:00 Objective response not everything, immune response contributes to overall survival 02:38:50 Rationale of melatonin-chemotherapy association in cancer
Increased efficacy
Prevention of lymphocyte damage, potebtial increased survival
Antioxidant induced increased cytotoxic activity of chemo and possible enhanced tumor rate
Prevention of toxicity
Thrombocytopenia, neurotoxicity, immunosuppression-related symptoms, asthenia
02:40:23 Melatonin increased efficacy amongst many chemos and cancers, taxol, gemcitabine etc
02:43:57
Rationale of melatonin-classical endocrine therapy
MLT stimulates endocrine receptor expression
Melatonin may inhibit tumor growth factor production
May reverse endocrine resistance
May have direct cytostatic action
Melatonin may modulate the expression of oncogenes and antioncogenes involved in regulating cancer cell hormone dependency
02:44:28 combined LHRH+ MLT therapy for metastatic prostate cancer
02:44:50 MBC results, Tamoxifen + 20mg melatonin
02:45:58 Tam + melatonin in non hormonal cancers
Future perspectives
MLT receptors
Other pineal hormones
Q&A
02:50:38
Q: type of light important?
Blaska: type of light at night very important to MLT suppression. Low light not so much.
Blue green most potent for suppression,low level red light ok, duration length important
Length of day extremes can effect
H: Doxo/Cis variation of circadian relationship seasonal. Incidence of cancer seasonal
Eg cervical peak seasonal and inverted phase in latitudes
Sexuality seasonality may influence, urbanization artificial lights, lack of light
Blaska: rodents nocturnal, humans diurnal. But both have nocturnal melatonin surge. (i.e. mouse circadian studies relevant) Artificial light during day much dimmer, night light brighter..modern life environment works against/reverses normal circadian tuning.>>
Q: depression and light
H: Tuning circadian response: : Darkness at night. MLT at night. bright light in morning, early exercise for early bed
Q: treatment
L: disease as well as chemo disrupts melatonin. Melatonin monitoring could be helpful biomarker
H: Beta blockers and other drugs inhibit melatonin
B: aging, then drugs, tv etc increase cancer in aging
H: aging might be tuned by tuning..healthy lifestyle
H: chronotherapy in dish dismissed in 70’s, focus became ablating rhythms instead of tapping into them
H: Melatonin peaks at puberty. By 40, very weak and then worse. Aging depression and cancer might be modulated by mlt
B: exercise and diet can effect nocturnal amount of mlt