CN103826645A

CN103826645A - Use of arsenic for cancer therapy protection

Info

Publication number: CN103826645A
Application number: CN201280034414.5A
Authority: CN
Inventors: Z-M.袁
Original assignee: TAXAS SYSTEM, University of, Regents of
Current assignee: TAXAS SYSTEM, University of, Regents of
Priority date: 2011-05-12
Filing date: 2012-05-11
Publication date: 2014-05-28
Also published as: CA2835631A1; WO2012155061A1; EP2707008A1; EP2707008A4; JP2014513698A

Abstract

A method of inhibiting, preventing, or reducing damage to non-cancerous cells in a human subject during chemotherapeutic treatment or radiation treatment of cancer cells in the human subject includes administering to the human subject arsenic and/or one or more compounds of arsenic in a therapeutically effective amount prior to treatment with radiation or one or more chemotherapeutic agents.

Description

The purposes of arsenic in treatment of cancer protection

about the research of federal government-funded or the statement of exploitation

The government of the subsidy CA085679 that the present invention authorizes in NIH (National Institutes of Health) completes under supporting.Government enjoys certain right in the present invention.

background of invention

2. description of related art

Cancer is animals and humans main causes of death.In the past during the decade, the combination of chemotherapy and X-ray therapy and operation has become the standard method for the treatment of patient's cancer under healing property and taking stopgap measures property background.Although X-ray therapy and chemotherapy are the successful modes for the treatment of of cancer, they do not have too big difference between cancerous cell and normal cell.Therefore, in the process of killing cancerous cell, radiation or chemotherapeutant also damage normal structure, cause general toxicity and harmful side effect, and this usually brings serious threat to cancer patient.Harmful side effect has also greatly limited maximal allowance dose.Although many-sided effort in past, avoids the effort of chemotherapy and radiotherapeutic toxicity not yet to produce significant result.

1. invention field

Present invention relates in general to the treatment of cancer.More particularly, the present invention relates to improve the side effect being caused by chemistry and radiation cancer therapy.

summary of the invention

On the one hand; the method that the present invention relates to suppress, prevents or reduce the infringement of the non-cancerous cell to people experimenter during the radiotherapy of people experimenter's cancerous cell, described method comprises with the protective number of approximately 1 μ g/kg/ days-Yue 125 μ g/kg/ days needs the people experimenter of radiotherapy with treatment cancer by the compound of one or more arsenic.In some embodiments, the protective number of the compound of one or more arsenic is approximately 31 μ g/kg/ days-Yue 125 μ g/kg/ days.After giving the compound of one or more arsenic, give people experimenter by radiation.In some embodiments, before giving people experimenter by radiotherapy, give people experimenter by arsenic trioxide.In some embodiments, before giving people experimenter by radiotherapy, at least one sky, gives people experimenter by the compound of one or more arsenic.In some embodiments, before giving people experimenter by radiation, give people experimenter at least three day by the compound of one or more arsenic every day.

On the other hand; the present invention relates to suppress, prevent or reduce during chemotherapy treatment people experimenter's cancerous cell the method for the infringement of the non-cancerous cell to people experimenter, described method comprises the people experimenter who with the protective number of approximately 1 μ g/kg/ days-Yue 125 μ g/kg/ days, the compound of one or more arsenic is needed to chemotherapy treatment.In some embodiments, the protective number of the compound of one or more arsenic is approximately 31 μ g/kg/ days-Yue 125 μ g/kg/ days.After giving the compound of one or more arsenic, give people experimenter by one or more chemotherapeutants.In some embodiments, before giving people experimenter by radiotherapy, give people experimenter by arsenic trioxide.In some embodiments, before giving people experimenter by one or more chemotherapeutants, at least one sky, gives people experimenter by the compound of one or more arsenic.In some embodiments, before giving people experimenter by one or more chemotherapeutants, give people experimenter at least three day by the compound of one or more arsenic every day.

On the other hand, the present invention relates to during chemotherapy or radiotherapy people experimenter's cancerous cell to suppress, prevent or reduce the method for the side effect in people experimenter, described method comprises needs chemotherapy or the radiotherapy people experimenter with treatment cancer by the compound of one or more arsenic.Before giving the compound of one or more arsenic, give people experimenter by one or more chemotherapeutants or radiation.Give the compound of one or more arsenic with the amount that is enough to suppress, prevent or be reduced in the side effect being caused by people experimenter's chemotherapy or radiotherapy while giving people experimenter by chemotherapeutant.In some embodiments, give the compound of one or more arsenic with the protective number of approximately 1 μ g/kg/ days-Yue 125 μ g/kg/ days.

Can be suppressed, prevent or the side effect that reduces comprises side effect relevant to gastronintestinal system; The side effect relevant with low red blood cell count(RBC); The side effect relevant with low numeration of leukocyte; Count relevant side effect with low platelet; Consume relevant side effect with medullary cell; The side effect relevant with cardiac toxicity; With the side effect relevant with alopecia.

accompanying drawing summary

The benefit of the following embodiment of describing in detail of nationality with reference to accompanying drawing, advantage of the present invention will be apparent to those skilled in the art, wherein:

Fig. 1 is illustrated in the effect of the male mice of arsenic pretreat to injection human lung carcinoma cell under various treatment conditions;

Fig. 2 is illustrated in the effect of the female mice of arsenic pretreat to injection human lung carcinoma cell under various treatment conditions;

Fig. 3 is illustrated in the effect of the female mice of arsenic pretreat to injection human breast cancer cell under various treatment conditions;

Fig. 4 is illustrated in the effect of the mice of arsenic pretreat to injection human colon cancer cell under various treatment conditions;

Fig. 5 is illustrated in arsenic pretreat under x x radiation x WT mice and p53 R172P is knocked in the effect comparison of mice;

Fig. 6 represents numeration of leukocyte after arsenic is to radiotherapy and the effect of small intestinal infringement.

Although the present invention can be subject to various modifications and alternative form, show its specific embodiment by example in the accompanying drawings, and will describe in detail in this article.Accompanying drawing can not to scale (NTS).But, should be appreciated that, accompanying drawing and detailed description are wherein not intended to limit the invention to disclosed concrete form, on the contrary, are intended to contain all modifications, equivalents and the alternative that fall in the spirit and scope of the present invention that the claims of enclosing limit.

detailed Description Of The Invention

Following definition is provided:

Term used herein " administration ", " giving " etc. are for provide compositions to experimenter in the situation that, generally refer to one or more pharmaceutical compositions, " OTC (over-the-counter) " (OTC) compositions or nutraceutical composition (nutraceutical composition) of combining with suitable delivery vector are provided to experimenter by any mode, make given compound realize the biological agent of one or more expections, the biological agent and giving for this reason of described compound.As limiting examples, can be in parenteral, subcutaneous, intravenous, coronary artery, rectum, intramuscular, intraperitoneal, send and give compositions through skin or buccal approach.Alternative or the while can give by oral route.The dosage giving by depend on receiver's age, health status, body weight and/or morbid state, treatment simultaneously kind (if any words), the character of therapeutic frequency and/or desired effect.The dosage of the pharmaceutically active compounds giving will depend on multiple factors, for example receiver's age, health status, body weight and/or morbid state, treatment simultaneously (if any words), character and the amplitude of therapeutic frequency and/or desired biological agent.

Term used herein " cancer " is defined as the growth of cell or breeds uncontrolled tissue, for example tumor.In a specific embodiment, tumor causes local invasion and attack and shifts.

Term used herein " chemotherapeutant " is defined as medicine, toxin, compound, compositions or the biological entities as treatment of cancer.

Term used herein " cytotoxic agent " is defined as medicine, toxin, compound, compositions or the biological entities for cell killing.In one embodiment, described cell is cancerous cell.

Term used herein " DNA damage agent (DNA-damaging agent) " is medicine, toxin, compound, compositions or the biological entities of damage nucleic acid.Damage can be any type damage to nucleic acid, for example, destroy one of DNA double helical molecule or two chains or cause the sudden change of one or more nucleotide.

Term used herein " medicine " is defined as medicament or the medicine of being used for the treatment of property treatment medical condition or disease.Medicine can or be treated type coupling with another kind of medicine, and in one embodiment, medicine is effective for treatment of cancer.

Term used herein " pharmaceutically or acceptable in pharmacology " refers to molecular entity and the compositions that in the time giving animal or human, can not produce harmful, allergic or other adverse effect.

Term used herein " pharmaceutically acceptable carrier " comprises any and all solvents, disperse medium, coating material, antibacterial agent and antifungal, isotonic agent and absorption delayer etc.

Term used herein for example " pharmaceutical composition ", " pharmaceutical dosage form ", " pharmaceutical preparation " etc. generally refer to the preparation that is suitable for one or more pharmaceutically active compounds of prescribed dose to be delivered to cell, cell mass, organ or tissue, animal or human.The method of pharmaceutically active compounds being mixed to pharmaceutical preparation is that this area is known.Be included within the suitable prescribed dose of pharmaceutically active compounds in pharmaceutical composition fixes on the common practitioner's in this area technical merit really for reaching required biological effect.Pharmaceutical composition can be used as sustained release forms or time controlled released dosage form provides.Described dosage form can discharge a large amount of compounds in required time from preparation, or the relatively constant amount that can guarantee to be present in the compound in dosage discharges in official hour.Term for example " sustained release ", " control and discharge " or " time controlled released " etc. are widely used in pharmaceutical field, and ordinary skill practitioner easily understands.Pharmaceutical preparation can be made into solid preparation, semi-solid preparation, gel, hydrogel adhesive, liquid preparation, solution, suspensoid, Emulsion, aerosol, powder or its combination.In pharmaceutical preparation, can comprise one or more normally carrier, antiseptic, correctives, excipient, coating material, stabilizing agent, binding agent, solvent and/or adjuvants of inertia in pharmacology.This area common practitioner easily understand, and comprises the pharmaceutically acceptable salt of compound in this term implication.The common practitioner in this area should also be clear that this term also comprises those pharmaceutical compositions of the mixture that contains two or more pharmaceutically active compounds (described compound for example gives as conjoint therapy).

Term used herein " experimenter " generally refers to mammal, refers to especially people.In one embodiment, the experimenter who accepts arsenical plans to carry out chemotherapy or radiotherapeutic experimenter.For example, experimenter has diagnosed suffer from cancer people patient or the animal of (to this cancer, chemotherapy or X-ray therapy are considered to be favourable treatment).

Term used herein " treatment " is defined as implements the practice for the treatment of to medical condition or disease.Treatment not necessarily provides completely cures, and is considered as effectively and if at least one symptom improves or is uprooted.In addition, treatment not necessarily provides the permanent improvement of morbid state or medical condition, but this is preferred.

Term " needs treatment ", " having it to need ", " can from such treatment, benefit " etc. are while being used in the case of the experimenter who gives pharmaceutically-active composite, generally refers to that the individuality made by suitable health care supplier or animal need maybe will to benefit from the treatment of specifying or the judgement of medical intervention.Such judgement can be made according to the various factors belonging in health care supplier professional skill field, described factor comprises following knowledge: because the medical intervention of available appointment is improved or the patient's condition for the treatment of, individuality or animal be ill, by ill or have an ill risk.

" side effect " relevant with chemotherapy or X-ray therapy includes but not limited to: stomachache, acid dyspepsia, the anti-stream of acid, alopecia (alopecia), anemia, inappetence, early full sense, arthralgia (arthralgia), weak, ataxia, azotemia, liver toxicity, bronchitis, constipation, cystitis, venous thrombosis (DVT), dyspepsia, dyspnea, edema, esophagitis, granulocytopenia, gynecomastia, hematoma, hemorrhagic cystitis, leukopenia, mucositis, myalgia, myocarditis, nephrotoxicity, neutrophilic granulocyte reduces, pancytopenia, pericarditis, pharyngitis, stomatitis, thrombocytopenia, xerostomia, dry skin, flushing, pigmentation, first changes, photosensitivity, radiation recovery (radiation recall) and erythra.In some embodiments, side effect comprises and reduces the side effect due to (a kind of low numeration of leukocyte) because of neutrophilic granulocyte.Low numeration of leukocyte can cause organism infection to increase.In some embodiments, side effect comprises because of effect secondary due to anemia (a kind of low red blood cell count(RBC)).Low red blood cell count(RBC) can cause for example having a headache and fatigue waits side effect.In some embodiments, side effect comprises because of effect secondary due to thrombocytopenia (a kind of low platelet counting).Low platelet counting can cause the side effect such as such as injury with blood-stasis, petechia and hemorrhage (such as nose, gingiva, rectum etc.) increase.Other side effect comprise gastrointestinal side-effect (for example feel sick, stomachache, angina abdominis, flatulence (inflation), acid dyspepsia, acid anti-stream, inappetence, early fullly feel etc.).Other side effect comprises alopecia (alopecia) and dermoreaction (for example dry skin, flushing, pigmentation, first change, photosensitivity, radiation recovery and erythra).

Except as otherwise noted, otherwise phrase " treatment effective dose " and " effective dose " are synonyms, mean to be enough to the amount of the compounds of this invention that improves the patient's condition, disease or the disease for the treatment of.Treat effective dose and effectively give determining of the relevant other factors of the compounds of this invention (comprising dosage form, route of administration and administration frequency) with the patient who treats to needs, can be depending on the details of the run into patient's condition, comprise treated patient and the patient's condition, specifically seriousness, the particular compound adopting, the concrete route of administration, the administration frequency that adopt of patient's the patient's condition and the concrete preparation adopting.The definite of effective therapeutic scheme in patient's treatment belonged in medical science or veterinary applications ordinary skill level.In the time of clinical use, effective dose can be by food and drug administration (U.S. Food and Drug Administration) or be equal to the amount that foreign mechanism is recommended.The amount that can combine the active component that produces single dosage form with carrier material becomes with treated mammalian hosts and concrete administering mode.

Term used herein " protective number " description and X-ray therapy or one or more chemotherapeutants simultaneously, the effective dose of the independent or sequential arsenical that gives experimenter, it is enough to reduce, prevent or otherwise improve X-ray therapy or chemotherapeutic drug to Normocellular harmful side effect.

Term used herein " tumor cell " is defined as the cell of pernicious (for example tumor or cancer).This cell can be positioned at the surface of tumor, tumor, or can associate with tumor.

When term used herein " reduction ", " inhibition " and " improvement " are used in the situation that regulating pathology or morbid state, generally refer at least a portion negative results that prevents and/or reduce morbid state.While use in the situation that of biochemistry event or approach, this term generally refers to amplitude or the active clean reduction of described approach.

Understand, the invention is not restricted to specific chemotherapy or X-ray therapy, it can change certainly.Also to understand, term used herein only for describe the object of specific embodiments, there is no mean restrictive.As this specification and the accompanying claims used, singulative " a ", " an " and " the " comprise odd number and plural object, unless context separately clearly states.

Just as skilled in the art to understand, for any and all objects, with regard to written explanation is provided, all scopes disclosed herein also comprise the combination of any and all possible subrange and subrange thereof especially.Any scope of enumerating can easily be considered as fully describing and can making described scope resolve at least equal bisection, 1/3rd, 1/4th, 1/5th, ten/first-class.As limiting examples, each scope of discussing herein can easily split into down 1/3rd, in 1/3rd and upper three/first-class.Should also be understood that as those skilled in the art for example " at the most ", " at least ", " being greater than ", " being less than " etc. of all terms comprise cited numeral, and refer to the scope that can continuous disassemble be divided into above-mentioned subrange.Finally, just as skilled in the art to understand, scope comprises each independent member.Therefore, for example, the group with 1-3 unit refers to the group with 1,2 or 3 unit.Similarly, the group that has a 1-5 unit refers to group having 1,2,3,4 or 5 unit etc.

The cancer of most of types can be with chemotherapy or radiation therapy treatment.Arsenic can be used for reducing the side effect relevant with the chemotherapy of cancer or radiation therapy treatment, described cancer is breast carcinoma, ovarian cancer, colorectal carcinoma, gastric cancer, pulmonary carcinoma, renal carcinoma, bladder cancer, carcinoma of prostate, uterus carcinoma, thyroid carcinoma, cancer of pancreas, cervical cancer, the esophageal carcinoma, mesothelioma for example, head and neck cancer, hepatocarcinoma, melanoma, the brain cancer, carcinoma vulvae, carcinoma of testis, sarcoma, intestinal cancer, skin carcinoma, leukemia and lymphoma.Various animal models (can be used to study the effectiveness of arsenic) and administration and the dosage of known described cancer.In some embodiments, experimenter accepts the arsenic of protective number, then accepts the chemotherapeutant of non-arsenical.

In one embodiment, provide such method, wherein by with give patient by chemotherapeutant and/or radiation with together with the compound of one or more arsenic, make cancer patient's chemotherapy or radiotherapeutic side effect suppressed.Effectively to reduce the amount of side effect, but than by the much smaller amount of swollen neoplastic amount other induction, give the compound of one or more arsenic.In some embodiments, before giving patient by chemotherapy or X-ray therapy, give the compound of one or more arsenic.In one embodiment, substantially in giving patient by chemotherapy or X-ray therapy or afterwards, give the compound of one or more arsenic.Can before and after, during chemotherapy or X-ray therapy, give the compound of one or more arsenic.The reduction of the order of severity of side effect improves and accepts the quality of life that chemotherapy or radiotherapeutic patient experience after chemotherapy and after X-ray therapy.The indication improving as described quality of life, observe compared with not carrying out the patient of arsenic pretreat, cancer patient has better appetite, better sleep, higher energy level, pain still less, gastrointestinal problems still less, alopecia still less, infection rate to reduce and desired body weight increase.

Can for example, on approaching any time point for the treatment of (chemotherapy or X-ray therapy), give arsenic, to produce needed protective effect.In one embodiment, before treating, for example 1-2 days, 1-3 days, 1-4 days, 1-5 days or 1-10 days before treating, give experimenter by arsenic.In some embodiments, before treating 1 day, 2 days, 3 days, 4 days or 5 days, give experimenter by arsenic.In a suitable embodiment, within first 3 days, give arsenic treating.During this period of time, giving can be once a day, occur for one day twice, one day three times, one day four times, one day six times or (for example giving by intravenous) occurs basic continous.

Conventionally the scope that, is enough to the effective dose of the arsenic composition of realizing protective effect is approximately 5 μ g/ kg body weight/skies, μ g/ kg body weight/sky-Yue 3,500.In some embodiments, the scope of effective dose is approximately 10 μ g/ kg body weight/skies, μ g/ kg body weight/sky-Yue 1,000.In other embodiments, the scope of effective dose is about 5-approximately 1,500 μ g/kg/ days, about 5-approximately 1,000 μ g/kg/ days, about 5-approximately 850 μ g/kg/ days, about 5-approximately 500 μ g/kg/ days, about 5-approximately 350 μ g/kg/ days, about 10-approximately 500 μ g/kg/ days, about 15-approximately 850 μ g/kg/ days or about 15-approximately 350 μ g/kg/ days.In other embodiments, the scope of effective dose is about 1-approximately 30 μ g/kg/ days, about 5-approximately 30 μ g/kg/ days, about 5-approximately 25 μ g/kg/ days, about 5-approximately 20 μ g/kg/ days, about 10-approximately 20 μ g/kg/ days or about 15-approximately 20 μ g/kg/ days.In suitable embodiment, dosage is approximately 15 μ g/kg/ days, approximately 20 μ g/kg/ days, approximately 25 μ g/kg/ days, approximately 30 μ g/kg/ days, approximately 35 μ g/kg/ days, approximately 40 μ g/kg/ days, approximately 50 μ g/kg/ days, approximately 100 μ g/kg/ days, approximately 150 μ g/kg/ days, approximately 250 μ g/kg/ days or approximately 500 μ g/kg/ days.

In some embodiments, the scope that is enough to the effective dose of the arsenic composition of the protective effect that realizes people is about 5-approximately 200 μ g/kg/ days, about 10-approximately 150 μ g/kg/ days, about 15-approximately 150 μ g/kg/ days, about 30-approximately 150 μ g/kg/ days, about 30-approximately 125 μ g/kg/ days, about 30-approximately 100 μ g/kg/ days, about 30-approximately 85 μ g/kg/ days, about 15-approximately 50 μ g/kg/ days; About 1-approximately 125 μ g/kg/ days, about 1.5-approximately 125 μ g/kg/ days, about 3-approximately 125 μ g/kg/ days, about 1.5-approximately 62.5 μ g/kg/ days, about 1-approximately 40 μ g/kg/ days or about 2-approximately 85 μ g/kg/ days.In some embodiments, the scope of the suitable total amount of the compound of one or more arsenic is about 31-approximately 125 μ g/kg/ days, about 31-approximately 85 μ g/kg/ days, about 35-approximately 80 μ g/kg/ days or about 40-approximately 70 μ g/kg/ days.

The example of the compound of operable arsenic includes but not limited to: arsenic oxide arsenoxide (III) (arsenic trioxide As ₂o ₃), arsenic oxide arsenoxide (V) (As ₂o ₅), arsenic selenide (III) (As ₂se ₃), arsenic sulfide (II) (As ₂s ₂), arsenic sulfide (III) (As ₂s ₃), arsenic sulfide (V) (As ₂o ₅), arsenic telluride (III) (As ₂te ₃), natrium arsenicum (Na ₂hAsO ₄), sodium arsenite (NaAsO ₂), Potassium acid arsenate (KH ₂asO ₄), tartaric acid sodium methanearsonate (NaC ₄h ₄asO ₆), Red Arsenic Sulfide (As ₄s ₄) and other derivant of arsenic.

In some embodiments, arsenic trioxide is used in the infringement that suppresses, reduces or prevent the non-cancerous cell to people experimenter during radiotherapy or chemotherapy treatment people experimenter's cancerous cell.Amount that can approximately 1 μ g/kg/ days-Yue 125 μ g/kg/ days scopes gives arsenic trioxide.In some embodiments, amount that can approximately 31 μ g/kg/ days-Yue 125 μ g/kg/ days scopes gives arsenic trioxide.In some embodiments, amount that can approximately 31 μ g/kg/ days-Yue 85 μ g/kg/ days scopes gives arsenic trioxide.In different embodiments, with do not give arsenic trioxide contrast experimenter or contrast population of subjects compare, arsenic trioxide can suppress, reduces or prevent the infringement at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50% or more to non-cancerous cell.

In some embodiments, sodium arsenite is used in the infringement that suppresses, reduces or prevent the non-cancerous cell to people experimenter during radiotherapy or chemotherapy treatment people experimenter's cancerous cell.Amount that can approximately 1 μ g/kg/ days-Yue 125 μ g/kg/ days scopes gives sodium arsenite.In some embodiments, amount that can approximately 31 μ g/kg/ days-Yue 125 μ g/kg/ days scopes gives sodium arsenite.In some embodiments, amount that can approximately 31 μ g/kg/ days-Yue 85 μ g/kg/ days scopes gives sodium arsenite.In some embodiments, amount that can approximately 31 μ g/kg/ days-Yue 65 μ g/kg/ days scopes gives sodium arsenite.In different embodiments, with do not give sodium arsenite contrast experimenter or contrast population of subjects compare, sodium arsenite can suppress, reduces or prevent the infringement at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50% or more to non-cancerous cell.

In some embodiments, arsenic trioxide is used for suppressing, reduce or preventing the side effect being caused by chemotherapeutant and/or X-ray therapy.Giving after arsenic trioxide, can give people experimenter by X-ray therapy or one or more chemotherapeutants.In some embodiments, before giving people experimenter by radiation or one or more chemotherapeutants at least one day, give people experimenter by arsenic trioxide.In some embodiments, before giving people experimenter by radiation or chemotherapeutant, give people experimenter by arsenic trioxide and reach at least three days.In different embodiments, with do not give arsenic trioxide contrast experimenter or contrast population of subjects compare, arsenic trioxide can suppress, reduces or prevent one or more side effect at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50% or more.

On the one hand, disclose by thering is xicity related treatment, together with giving the arsenic of one or more protection dosage with the method for the treatment of experimenter's morbid state before giving the time of described treatment.The arsenical that gives protective number accompanies by one or more side effect relevant with chemotherapy or X-ray therapy and is improved.For example, be used for the treatment of the chemotherapy of cancer and some immune disorders and X-ray therapy and can cause that pancytopenia or anemia, neutrophilic granulocyte reduce and thrombocytopenic combination.Therefore, the increase of hematopoietic cell or displacement are usually conclusive for the success of described treatment.

The effect that arsenic is given to experimenter is the toxicity (for example hemopoietic toxicity) that reduces treatment, therefore allows high dose and the intensive scheme of dosage of the therapeutic scheme that is ready to use in particular subject.The overall benefit of implementing this embodiment is to give experimenter by arsenic to reduce or reduce the toxicity for the treatment of, for example hemopoietic toxicity.Therefore, can change acceptable dosage on the maximum therapy of various therapeutic modalities.In some cases, with respect to not giving acceptable dosage on experimenter's the maximum therapy of arsenic before treatment, can improve acceptable dosage on the maximum therapy for the treatment of.

In one embodiment, the arsenic that gives protective number accompanies by bone marrow situation after chemotherapy or X-ray therapy expose to be improved.If one or more in following situations occur, experimenter's bone marrow situation improves: for example, in cancerous cell therapy (X-ray therapy and/or chemotherapy) if after in experimenter the density of medullary cell be greater than the density of with arsenic, experimenter not being carried out pretreat before cancerous cell therapy; If in experimenter's bone marrow, the density of CFU-GM or stem cell is greater than the density of with arsenic, experimenter not being carried out pretreat before cancerous cell therapy after cancerous cell therapy; For example, in cancerous cell therapy (X-ray therapy and/or chemotherapy) if after the quality of experimenter's myeloid tissue be greater than the quality of with arsenic, experimenter not being carried out pretreat before cancerous cell therapy; Or for example, in cancerous cell therapy (X-ray therapy and/or chemotherapy) if after in experimenter the speed of proliferation of bone marrow cells be greater than the speed of with arsenic, experimenter not being carried out pretreat before cancerous cell therapy.The mensuration of effectiveness can be carried out with any time after chemotherapy or radiopharmaceutical agent treatment.For example, the mensuration of effectiveness can for example, be carried out after described medicament (chemotherapeutant or radiation) is delivered to experimenter for 1,2,3,4,5,6,7,8,9,10 day or more days.For this analysis, bone marrow sample can be available from any part of bone marrow in experimenter's body.If for by result with do not carry out the desired result of pretreat with arsenic and compare, can be individual from one or more contrasts, preferably collection data from number of individual (accept same or similar chemotherapy or X-ray therapy but do not accept arsenic).Control population is suitable for example, to be treated because of the identical patient's condition (identical type of cancer).Compared with control population, if produce any benefit whatever, amount is protective number.For example, for example, for example, if be subject to the bone marrow condition parameter (specifying the multiplication rate of CFU-GM type) of the individual or normal value that is subject to treatment group to there is its value or meansigma methods to approach contrast individuality or matched group for the treatment of (higher than) or meansigma methods, be subject to treatment individual or improved by the bone marrow situation for the treatment of group.Suitably time, can be by statistical method optional use in this analysis.In different embodiments, protection effective dose can be and improves bone marrow situation at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50% or higher amount.

For the X-ray therapy in chemotherapy and some situation, on maximum therapy, acceptable dosage can be measured by monitoring experimenter's complete blood count (CBC) (" CBC ").Can show low red blood cell count(RBC), low numeration of leukocyte, low platelet counting or its combination to the damage of experimenter's bone marrow.In general, the scope of normocyte counting is approximately 450 Wan-Yue 6,000,000/microlitre blood.Can show that lower than the about red blood cell count(RBC) of 4,000,000/microlitre blood chemotherapy dosage and/or radiological dose are higher than acceptable dosage on maximum therapy.In general, the scope of normal numeration of leukocyte is approximately 4,000-approximately 11,000/ microlitre blood.Can show that lower than the numeration of leukocyte of approximately 3,500/ microlitre blood chemotherapy dosage and/or radiological dose are higher than acceptable dosage on maximum therapy.In general, the scope of orthoplastocyte counting is approximately 150, approximately 400,000 cell/microlitre blood of 000-.Platelet cell counting lower than approximately 50,000/ microlitre blood can show that chemotherapy dosage and/or radiological dose are higher than acceptable dosage on maximum therapy.Be described in Gurey for the method for determining acceptable dosage on maximum therapy, " How to calculate the dose of chemotherapy the dosage of chemistry therapy (how) ", British Journal of Cancer (2002), 86,1297-1302, it is incorporated herein by reference.

In some embodiments, therefore can, by monitoring experimenter's CBC, determine acceptable amount on maximum therapy.Find, can be by giving the compound of one or more arsenic of experimenter before giving one or more chemotherapeutants, be increased in to cause that one or more cell countings drop to the general acceptable amount of spendable chemotherapeutant before below horizontal.In general, the amount that increases the chemotherapeutant that gives experimenter will improve the effect (for example improve the destroyed speed of cancerous cell and/or reduce the incidence rate recurring) for the treatment of.

Also find, can be by give experimenter by the compound of one or more arsenic before giving experimenter by radiation, increase during X-ray therapy cause one or more cell countings drop to lower than general acceptable level before operable radiological dose.In general, the amount that increases the radiation that gives experimenter will improve the effect (for example improve the destroyed speed of cancerous cell and/or reduce the incidence rate recurring) for the treatment of.

Can utilize other factors to determine acceptable dosage on maximum therapy.For example, chemotherapy and radiotherapeutic side effect can be the damages to intestinal mucosa.This can also be X-ray therapy and chemotherapeutic dose limitation side effect, because can affect the ability of body absorption nutrient to the damage of intestinal mucosa.In some embodiments, on the maximum therapy of cancerous cell therapy, acceptable dosage can be the dosage with the damage to intestinal mucosa that can receiving amount.In some embodiments, the body weight that can monitor experimenter is to determine the state of intestinal mucosa.For example, significantly lose weight (for example during treatment from experimenter's inchoate aspect restatement, lose weight and exceed 3 pounds) can show the unacceptable damage to intestinal mucosa.Find, can be by giving the compound of one or more arsenic of experimenter before giving one or more chemotherapeutants, be increased in to cause the amount to spendable chemotherapeutant before the unacceptable damage of intestinal mucosa.Also find, can be by give the compound of one or more arsenic of experimenter before giving experimenter by radiation, increase during X-ray therapy spendable radiological dose before causing the unacceptable damage of intestinal mucosa.

Radiotherapy dose and the factor comprise radiation and the ripple of inducing DNA damage, such as γ-radiation, X ray, ultraviolet radiation, microwave, electron emission, radiosiotope etc.Can realize treatment by irradiate localization tumor locus by above-mentioned radiation formula.Very likely be that these all factors cause following significantly damage: the precursor of DNA, DNA, DNA copy with repair ability and chromosomal assembling and maintain.

The dosage range of X ray is that 50-200 roentgen's the daily dose of the time (3-4 week) from continuing a segment length is to 2000-6000 roentgen's single dose.Radioisotopic dosage range significantly changes, and depends on isotopic half life, the intensity of institute's emitted radiation and the picked-up of type and tumor cell.

Chemotherapeutant comprise direct crosslinked DNA agent, the intercalation of DNA agent and synthesize by affect nucleic acid the agent that causes chromosome and Mitotic aberration.The example of chemotherapeutant includes but not limited to: doxorubicin, daunorubicin, mitomycin, actinomycin D, bleomycin, cisplatin, etoposide, tumor necrosis factor, taxol, vincristine, vinblastine, carmustine, melphalan, cyclophosphamide, chlorambucil, busulfan, fluorouracil (" 5FU ") and lomustine.After the compound pretreat patient with one or more arsenic, any of these agents can be used alone, or with other agent coupling.Patient reduces intensity and the generation of many side effect of above-mentioned chemotherapeutant with the compound pretreat of one or more arsenic, and does not significantly suppress effect of this class agent.

The agent of directly crosslinked nucleic acid (especially DNA) is expected, and is shown that herein result is the DNA damage that causes synergistic antitumor combination.Can use the agents such as such as cisplatin and other DNA alkylating agent.

The agent of damage dna also comprises the compound that disturbs DNA replication dna, mitosis and chromosome separation.The example of these compounds comprises doxorubicin (also claiming amycin), etoposide (also claiming VP-16), verapamil, podophyllotoxin etc.These compounds that are widely used in oncotherapy under clinical setting give by intravenous push, and for amycin, dosage range is with 21 days interval 25-75 mg/m ², for etoposide, be intravenous or oral 35-100 mg/m ².

Doxorubicin hydrochloride; 5,12-aphthacene diketone, (8s-cis)-10-((3-amino-2; 3; 6-tri-deoxies-a-L-lyxose-own pyranose) oxygen base)-7,8,9; 10-tetrahydrochysene-6; 8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxyl group-hydrochlorate (hydroxydaunomycin hydrochloride, amycin), for broad-spectrum anti-tumor medicine.It is combined with DNA, suppresses nucleic acid synthetic, suppresses mitosis and promotes chromosomal aberration.

While giving separately, it is the choice drug that is used for the treatment of thyroid adenoma and primary hepatoma.It is the component that is used for the treatment of 31 kinds of first-selected combinations of following cancer: ovarian cancer, adenomyoma and mastadenoma, bronchus oat-cell carcinoma, nonsmall-cell lung cancer, adenocarcinoma of stomach, retinoblastoma, neuroblastoma, mycosis fungoides, cancer of pancreas, carcinoma of prostate, bladder cancer, myeloma, diffusivity histocytic lymphoma, wilms' tumor (Wilms'tumor), Hodgkin (Hodgkin's disease), adrenal tumor, osteogenic sarcoma, soft tissue sarcoma, Ewing sarcoma (Ewing's sarcoma), rhabdomyosarcoma and acute lymphoblastic leukemia.It is the drug candidate that is used for the treatment of islet-cell carcinoma, cervical cancer, carcinoma of testis and adrenocortical carcinoma.It or immunosuppressant.

Doxorubicin absorption difference, intravenous gives conventionally.Pharmacokinetics is multi-region chamber.Distribute and there is mutually the half life of 12 minutes and 3.3 hours.Removing half life is approximately 30 hours.40-50% secretes to bile.The metabolism in liver of remaining major part, part becomes active metabolite (doxorubicin alcohol (doxorubicinol)), but minority percentage ratio is secreted into urine.In the time existing liver impaired, dosage is conventionally suppressed.

Suitable dosage is adult's intravenous 60-75 mg/m ²by the interval of 21 days, or continuous 2 days or 3 day every day 25-30 mg/m ²repeat with the intervals of 3 or 4 weeks, or 20 mg/m ²weekly.In the time that existence invades by previous chemotherapy or tumor bone marrow the previous bone marrow depression causing, or in the time of described medicine and other bone marrow generation inhibition drug regimen, in gerontal patient, should use lowest dose level.If serum bilirubin is between 1.2 and 3 mg/dL, dosage should reduce by 50%, if higher than 3 mg/dL, dosage reduces by 75%.In the patient with normal cardiac function, lifelong accumulated dose should not exceed 550 mg/m ², and in the people who accepts mediastinum radiation, should not exceed 400 mg/m ².Or, for three days on end every days 30 mg/m ², every 4 weeks repeat.Exemplary dose can be 10 mg/m ², 20 mg/m ², 30 mg/m ², 50 mg/m ², 100 mg/m ², 150 mg/m ², 175 mg/m ², 200 mg/m ², 225 mg/m ², 250 mg/m ², 275 mg/m ², 300 mg/m ², 350 mg/m ², 400 mg/m ², 425 mg/m ², 450 mg/m ², 475 mg/m ², 500 mg/m ².Certainly, all these dosage are all exemplary, and the same expection of any dosage between these points is for the present invention.

Daunorubicin hydrochloride, 5,12-aphthacene diketone, (8S-cis)-8-acetyl group-10-((3-amino-2,3,6-, tri-deoxies-a-1-lyxose-own pyranose) oxygen base)-7,8,9,10-tetrahydrochysene-6,8,11-trihydroxy-10-methoxyl group hydrochlorate; Also claiming cerubidine, is commercial obtainable.In the daunorubicin intercalation of DNA, the RNA polymerase that blocking dna instructs, and it is synthetic to suppress DNA.It is the synthetic dosage prevention cell division of interfere RNA not.

While combination with other medicines, it is included in the first-selected chemotherapy of the acute stage of Aduit Acute Myeloid Leukemia (for inducer remission), acute lymphoblastic leukemia and chronic myelocytic leukemia.Oral absorption is poor, must give by intravenous.The half life that distributes is 45 minutes, and elimination half life is about 19 hours.Approximately 27 hours half lifes of its active metabolite (duborimycin (daunorubicinol)).The metabolism in liver of daunorubicin major part, is also secreted into (approximately 40%) in bile.In the time of liver or renal insufficiency, dosage must reduce.

Suitable dosage is (alkali equivalent (base equivalent)) 60 years old following adult's intravenous 45 mg/m ²/ day (more than 60 years old patient 30 mg/m ²) within every 3 weeks or 4 weeks, continue 1,2 or 3 day, or within 0.8 mg/kg/ days every 3 weeks or 4 weeks, continue 3-6 days; Give all the life should not exceed 550 mg/m ²unless, not if any 450 mg/m only of breast radiation ²; Child, 25 mg/m ²weekly, unless the age is less than 2 years old or surface is less than 0.5 m, in this case, use the adult's scheme based on body weight.In injectable dosage form (alkali equivalent), can use 20 mg (because this alkali is equivalent to the hydrochlorate of 21.4 mg).Exemplary dose can be 10 mg/m ², 20 mg/m ², 30 mg/m ², 50 mg/m ², 100 mg/m ², 150 mg/m ², 175 mg/m ², 200 mg/m ², 225 mg/m ², 250 mg/m ², 275 mg/m ², 300 mg/m ², 350 mg/m ², 400 mg/m ², 425 mg/m ², 450 mg/m ², 475 mg/m ², 500 mg/m ².Certainly, these dosage are exemplary, and the same expection of any dosage between these points is for the present invention.

Mitomycin (also claiming mutamycin and/or Mitomycin-C) be a kind of from streptomyces caespitosus ( streptomyces caespitosus) fluid medium in the antibiotic that separates, it is proved has anti-tumor activity.This compound is heat-staple, has high-melting-point, and is soluble in organic solvent.

Mitomycin selectivity suppresses the synthetic of DNA (deoxyribonucleic acid) (DNA).Guanine is relevant with the crosslinked degree of mitomycin induction with cytosine content.Under this medicine of high concentration, cell RNA and protein synthesis are also suppressed.

In people, after intravenous gives, mitomycin is removed fast from serum.After 30 mg inject, it is 17 minutes that reduction serum-concentration reached for 50% needed time.After 30 mg, 20 mg or 10 mg I.V. injection, maximum serum-concentration is respectively 2.4 mg/mL, 1.7 mg/mL and 0.52 mg/mL.Mainly remove by metabolism in liver, but metabolism also occurs in other tissue.Clearance rate and maximum serum-concentration are inversely proportional to, because think that degradation pathway is by saturated.

The mitomycin of approximately 10% dosage is secreted in urine steadily.Because metabolic pathway is saturated under relative low dosage, the dosage percentage ratio of secretion in urine increases and improves with dosage.In child, the secretion of the mitomycin that intravenous gives is similar.

Actinomycin D (Dactinomycin) (50-76-0); C ₆₂h ₈₆n ₁₂o ₁₆(1255.43) be the antitumor drug that suppresses the RNA polymerase that relies on DNA.It is the component that is used for the treatment of the first-selection combination of choriocarcinoma, embryonal rhabdomyosarcoma, testicular tumor and wilms' tumor.The tumor that can not respond systemic treatment is perfused with response to part sometimes.Actinomycin D strengthens X-ray therapy.It is Secondary cases (spreading out of) immunosuppressant.

Actinomycin D and first operation, X-ray therapy and other medicines (particularly vincristine and cyclophosphamide) coupling.In ewing's tumor, Kaposi sarcoma (Kaposi's sarcoma) and soft tissue sarcoma, be also noted that anti-tumor activity.Actinomycin D may be effectively in the women who suffers from choriocarcinoma late case.In metastatic testicular cancer patient, it is also producing consistent reaction with the combination of chlorambucil and methotrexate.In the patient who suffers from Hodgkin (Hodgkin's disease) and non-Hodgkin lymphoma, sometimes can be observed reaction.Actinomycin D is also used to Immunosuppression and replys, particularly the repulsion of renal transplantation thing.

The dosage of half is intactly secreted in bile, and 10% is secreted in urine; Half life is approximately 36 hours.Medicine does not pass through blood brain barrier.Actinomycin D is applied with lyophilized powder (every bottle 0/5 mg).Common daily dose is 10-15 mg/kg; Intravenous administration 5 days; If do not run into toxicity phenomenon, interval that can 3-4 week gives the extra course for the treatment of.Give child and inject 100-400 mg every day, continue 10-14 days; In other scheme, use the 3-6 mg/kg weekly maintenance dose of 125 mg/kg and 7.5 mg/kg altogether.Although medicine is given in intravenous infusion pipe safer, in the case of preventing from abandoning syringe needle for extract medicine from bottle to avoid, subcutaneous reaction, also giving direct intravenous injection.Exemplary dose can be 100 mg/m ², 150 mg/m ², 175 mg/m ², 200 mg/m ², 225 mg/m ², 250 mg/m ², 275 mg/m ², 300 mg/m ², 350 mg/m ², 400 mg/m ², 425 mg/m ², 450 mg/m ², 475 mg/m ², 500 mg/m ².Certainly, all these dosage are all exemplary, and the same expection of any dosage between these points is for the present invention.

Bleomycin be from streptomyces verticillus ( streptomyces verticillus) mixture of cytotoxicity glycopeptide antibiotic of strains separation.During it is soluble in water.

Although do not know the definite mechanism of action of bleomycin, obtainable evidence seems to show that the Main Patterns acting on is to suppress DNA to synthesize, and some of them evidence is less suppress RNA and protein synthetic.

In mice, in skin, lung, kidney, peritoneum and lymphsystem, there is the bleomycin of high concentration.Find that the tumor cell of skin and lung has the bleomycin of high concentration, this is contrary with the low concentration existing in hemopoietic tissue.The low concentration bleomycin existing in bone marrow may be relevant with the high-level bleomycin digestive enzyme existing in this tissue.

In the creatinine clearance >35 patient of mL/ minute, end removing half life is approximately 115 minutes eventually for the serum of bleomycin or blood plasma.In the creatinine clearance <35 patient of mL/ minute, end removing half life, reduces and is exponent increase with creatinine clearance eventually for blood plasma or serum.In people, the 60%-70% of the dosage that gives reproduces as active bleomycin in urine.

Bleomycin should be considered as palliative treatment.Show, it in the treatment of following tumor as independent agent or be useful in the combination of attested and other approved chemotherapeutant: for example head and neck of squamous cell carcinoma (comprising oral cavity, tongue, tonsil, nasopharynx, oropharynx, nasal sinuses, palate, lip, oral mucosa, gingiva, epiglottis, larynx), skin, penis, cervix uteri and pudendum.It is also used for the treatment of lymphoma and carcinoma of testis.

Due to the probability of anaphylactoid reaction, therefore for two dosage at first, Lymphoma should be with 2 units or still less unit treatment.If occurred without acute reaction, dosage can observe a usual practice.

The improvement of Hodgkin and testicular tumor was rapidly with significant in 2 weeks.If then do not observe improvement, improve and can not occur.Squamous cell carcinoma more slowly reacts, and sometimes needs to reach 3 weeks noticing before any improvement.

Bleomycin can give by intramuscular, intravenous or subcutaneous route.

Cisplatin has been widely used in treatment cancer, for example metastatic testicular cancer or ovarian cancer, advanced bladder carcinoma, head and neck cancer, cervical cancer, pulmonary carcinoma or other tumor.Cisplatin can be alone or with other agent coupling, its effective dose for clinical practice is 15-20 mg/m ²within every 3 weeks, continue 5 days totally 3 courses for the treatment of.Exemplary dose can be 0.50 mg/m ², 1.0 mg/m ², 1.50 mg/m ², 1.75 mg/m ², 2.0 mg/m ², 3.0 mg/m ², 4.0 mg/m ², 5.0 mg/m ², 10 mg/m ².Certainly, all these dosage are all exemplary, and the same expection of any dosage between these points is for the present invention.

Cisplatin can not oral absorption, therefore must by intravenous, subcutaneous, tumor or peritoneal injection send.

Of the present invention, aspect some, cisplatin and emodin or emodin sample compound combination are used for the treatment of nonsmall-cell lung cancer.But obviously, the combination of cisplatin and emodin and/or emodin sample compound can be used for treating the cancer of any other neu mediation.

Etoposide is also called VP16, is mainly used to treat testicular tumor, and is used for small cell lung cancer with cisplatin combination with bleomycin and cisplatin combination.It also has activity for non-Hodgkin lymphoma, acute nonlymphocytic leukemia, breast carcinoma and the Kaposi sarcoma relevant with acquired immune deficiency syndrome (AIDS) (AIDS).

Etoposide can be used as the solution (20 mg/ml) giving for intravenous and obtains as the 50-mg liquid-filling capsule agent for oral.For small cell lung cancer, intravenous dosages (in combination treatment) can reach 100 mg/m ²or be low to moderate 2 mg/m ², routine is also used mg/m every days 35 ²continue 4 days, to mg/m every days 50 ²continue 5 days.In the time of oral giving, dosage should double.Therefore can be up to 200-250 mg/m for the dosage of small cell lung cancer ².Intravenous dosages (at combination treatment) for carcinoma of testis is 50-100 mg/m every day ²continue 5 days, or the next day 100 mg/m ²continue 3 dosage.Common every 3-4 repetitive therapy cycle in week.Should during infusion, slowly give medicine at 30-60 minute to avoid hypotension and bronchospasm, this may be due to the solvent because using in preparation.

Tumor necrosis factor (TNF; Cachectin) be a kind of glycoprotein, it kills the cancerous cell of some kind, and the active cell factor produces, and activating macrophage and endotheliocyte promote the generation of collagen and collagenase; Be a kind of inflammatory mediator, but also be the medium of septic shock; And promote catabolism, heating and sleep.Some infectants (infectious agent) cause tumor regression by stimulating TNF to produce.TNF may have toxicity when alone with effective dose, makes the preferred plan may be by be used in combination TNF compared with low dosage and other medicines.Gamma interferon increases its immunosuppressive action, and it may be dangerous making this combination.The heterozygote of also finding TNF and interferon-' alpha ' has active anticancer.

Taxol is experimental antimitotic drug, its from Chinese ash (ash tree) yewtree ( taxus brevifolia) bark separate.It is in conjunction with tubulin (being different from the site that catharanthus alkaloid utilizes) and promote the assembling of microtubule.Taxol is just carrying out clinical evaluation at present; It has the activity for malignant melanoma and ovarian cancer.Maximal dose is 30 mg/m ²/ day lasting 5 days or 210-250 mg/m ²within every 3 weeks, give once.Certainly, all these dosage are all exemplary, and the same expection of any dosage between these points is for the present invention.Fig. 6 is the diagram that show peptide and the liposome that carries anticarcinogen taxol are puted together by Polyethylene Glycol joint.

Vincristine is blocked mitosis and is produced and stops mid-term.Probably most of biological activity of this medicine can be explained by its following ability: become the ability of microtubule with tubulin specific binding blocking protein polymerization.The destruction of the microtubule by mitotic apparatus, cell division stopped in mid-term.By inference, during mitosis, can not correctly separate chromosome and cause cell death.

Vincristine makes this medicament unusual in antitumor drug to normal marrow cell with epithelial relative hypotoxicity, and it is often included in the combination with other myelosuppressive.

Report oral and had unpredictable absorption after giving vinblastine or vincristine.Under common clinical dosage, in blood plasma, the peak concentration of each medicine is about 0.4 mM.

Vinblastine and vincristine are combined with plasma proteins.They concentrate in platelet in a large number, in leukocyte and erythrocyte to less degree.

Vincristine has the heterogeneous cleaning module from blood plasma; End half life is approximately 24 hours eventually.The metabolism in liver of this medicine, but do not identify biologically active derivatives.In hepatic insufficiency patient, should reduce dosage.If the bilirubin concentration in blood plasma is greater than 3 mg/dl (approximately 50 mM), show that dosage is reduced by least 50%.

Can obtain the vincristine sulfate as the solution for intravenous injection (1 mg/ml).It is the treatment selection that causes that at present leukemia of children is alleviated that vincristine uses together with corticosteroids; The optimal dose of these medicines shows as intravenous vincristine 2 mg/m weekly ²body surface area, and every day oral prednisolone 40 mg/m ².Suffer from the adult patients of Hodgkin or non-Hodgkin lymphoma and conventionally accept the part of vincristine as integration scenario.When for MOPP scheme, the recommended dose of vincristine is 1.4 mg/m ².Suffer from leukemic child and seem better to the toleration of high dose vincristine than adult, adult may suffer serious neurotoxicity.More frequent or give this medicine with high dose more than every 7 days, seem to increase the weight of intoxicating phenomenon and in reaction rate without proportional improvement.Also should adopt preventive measure to avoid intravenous to give exosmosing during vincristine.With the dosage of the dosage several times with suitable toxicity that can intravenous give, vincristine (and vinblastine) is infused in the tremulous pulse blood supply of tumor.

Vincristine is effective in Hodgkin and other lymphoma.Although when separately for Hodgkin, vincristine seems than the less a little benefit of vinblastine, but in the time using together with chlormethine, prednisolone and procarbazine (so-called MOPP scheme), for this sick late period (III and IV) be preferred treatment.In non-Hodgkin lymphoma, vincristine is a kind of important medicament, special in the time that cyclophosphamide, bleomycin, doxorubicin use together with prednisolone.In Lymphocytic leukemia, vincristine is more useful than vinblastine.Report the useful reaction in the patient who suffers from various other tumors, particularly wilms' tumor, neuroblastoma, cerebroma, rhabdomyosarcoma and breast carcinoma, bladder cancer and masculinity and femininity reproductive system cancer.

Can be determined by clinicist the dosage that uses vincristine according to each patient's needs.Can give 0.01-0.03 mg/kg or 0.4-1.4 mg/m ², or also can give 1.5-2 mg/m ².Or can give 0.02 mg/m ², 0.05 mg/m ², 0.06 mg/m ², 0.07 mg/m ², 0.08 mg/m ², 0.1 mg/m ², 0.12 mg/m ², 0.14 mg/m ², 0.15 mg/m ², 0.2 mg/m ², 0.25 mg/m ²as constant intravenous infusion.Certainly, all these dosage are all exemplary, and the same expection of any dosage between these points is for the present invention.

When cell when incubation, occurs that microtubule dissolves together with vinblastine.Report oral and had unpredictable absorption after giving vinblastine or vincristine.Under common clinical dosage, in blood plasma, the peak concentration of each medicine is approximately 0.4 mM.Vinblastine and vincristine are combined with plasma proteins.They concentrate in platelet in a large number, in leukocyte and erythrocyte to less degree.

After intravenous injection, vinblastine has the heterogeneous cleaning module from blood plasma; After distribution, medicine disappears from blood plasma, and its half life is approximately 1 and 20 hour.

Vinblastine in liver metabolism biologically to activate the de-acetyl vinblastine of derivant.In urine, former state detects approximately 15% of given dosage, and after bile excretion, approximately 10% reproduces in feces.In hepatic insufficiency patient, should reduce dosage.If the bilirubin concentration in blood plasma is greater than 3 mg/dl (approximately 50 mM), show that dosage is reduced by least 50%.

Vinblastine sulfate can obtain by injection preparation.Give medicine at intravenous; Must take special preventive measure to ooze out for subcutaneous, because this can cause nociceptive stimulus and ulcer.Medicine should not be expelled to the impaired acra of circulation.After the single dose of 0.3 mg/kg body weight, it is maximum that bone marrow depression reached in 7-10 days.If do not reach leukopenia (approximately 3000 cell/mm of medium level ³), can progressively improve every weekly dose by the increment of 0.05 mg/kg body weight.In the scheme of designed treatment carcinoma of testis, use vinblastine with the dosage of every 3 weeks 0.3 mg/kg, do not consider cytometry or toxicity.

The most important clinical practice of vinblastine is and bleomycin curative therapy transitivity testicular tumor together with cisplatin.Reported in various lymphoma, particularly the useful reaction in Hodgkin is wherein recorded and is significantly improved in 50-90% case.In the time that lymphoma is reactionless to alkylating agent, the effect of vinblastine in most of lymphoma do not reduce.It also has activity in Kaposi sarcoma, neuroblastoma and Letterer-Siwe disease (histiocytosis X) and women with breast cancer and choriocarcinoma.

Clinicist can determine the dosage that uses vinblastine according to each patient's needs.0.1-0.3 mg/kg can be given, or also 1.5-2 mg/m can be given ².Or, can give 0.1 mg/m ², 0.12 mg/m ², 0.14 mg/m ², 0.15 mg/m ², 0.2 mg/m ², 0.25 mg/m ², 0.5 mg/m ², 1.0 mg/m ², 1.2 mg/m ², 1.4 mg/m ², 1.5 mg/m ², 2.0 mg/m ², 2.5 mg/m ², 5.0 mg/m ², 6 mg/m ², 8 mg/m ², 9 mg/m ², 10 mg/m ², 20 mg/m ².Certainly, all these dosage are all exemplary, and the same expection of any dosage between these points is for the present invention.

Carmustine (aseptic carmustine) is one of nitrosoureas being used for the treatment of some oncosis.It is 1,3 pair of (2-chloroethyl)-1-nitroso ureas.It is the light yellow thin slice of lyophilizing or the coagula that molecular weight is 214.06.It is highly dissolved in alcohol and lipid, not soluble in water.Carmustine, after redissolving by recommendation, gives by intravenous infusion.Aseptic carmustine obtains with the freeze dried substance of 100 mg single dose bottles conventionally.

Although it is generally acknowledged that carmustine makes DNA and RNA alkylation, it does not have cross tolerance with other alkylating agent (alkylator).As other nitroso ureas, it can also be by making aminoacid carbamoylation in protein suppress the enzyme process of several keys.

Show that carmustine is in the cerebromas such as such as glioblastoma, brain stem glioma, medullobladyoma, astrocytoma, ependymoma and metastatic brain tumor, with independent agent or that established and combination treatment other granted chemotherapeutant, as palliative treatment.It is also used in combination to treat multiple myeloma with prednisolone.Confirmed carmustine as recurrence when with first therapy for treating or in the nullvalent patient of first therapy with the secondary therapy of other granted drug regimen, the helpfulness in Hodgkin and non-Hodgkin lymphoma treatment.

In the patient who does not receive treatment before, carmustine is every 6 weeks intravenous 150-200 mg/m as the recommended dose of single agent ².This can be single dose or is divided into and injects for example 75-100 mg/m every day ²over continuous 2 days, give.When carmustine and other bone marrow depression drug regimen use or exhaust for its bone marrow deposit patient time, should correspondingly adjust dosage.Dosage after predose should be adjusted hematology's reaction of dosage before according to patient.Certainly will understand, the present invention can use other dosage, for example 10 mg/m ², 20 mg/m ², 30 mg/m ², 40 mg/m ², 50 mg/m ², 60 mg/m ², 70 mg/m ², 80 mg/m ², 90 mg/m ², 100 mg/m ².Technical staff can be with reference to " Remington's Pharmaceutical Sciences ", the 17th edition.Some must occur dosage changes, and this depends on experimenter's to be treated situation.Under any circumstance, the people of responsible administration will determine the appropriate dose of individual subjects.

Melphalan also claims L-Sarcolysinum, Phenylalanin-Lost, melphalan, L-PAM or L-Sarcolysin, is the phenylalanine derivative of chlormethine.Melphalan is a kind of difunctionality alkylating agent, and it has activity for selectivity people oncosis.It is chemically being called 4-(two (2-chloroethyl) amino)-L-Phe.

Melphalan is the active L-isomer of described compound, synthetic first by Bergel and Stock in nineteen fifty-three; D-isomer, is called medphalan, has compared with low activity, and the needed dosage of chromosome generation effect is greater than with the needed dosage of L-isomer for some animal tumor.Raceme (DL-) form is called merphalan or Sarcolysin.Melphalan is water insoluble, its pKa ₁be about 2.1.Melphalan can obtain for the oral tablet form that gives, and has been used for treating multiple myeloma.

Available evidence shows, approximately 1/3rd multiple myeloma patients to half show favourable reaction to this medicine oral.

Melphalan has been used for the treatment of ovarian epithelial carcinoma.Treatment ovarian cancer a kind of common scheme be using every day 0.2 mg/kg dosage continue within 5 days, give melphalan as the single course for the treatment of.According to hematology's toleration, every 4-5 week repeats a treatment.Or the dosage of melphalan used can be low to moderate 0.05 mg/kg/ days or high to any dosage or above-mentioned these dosage between 3 mg/kg/ days or these dosage.Must there will be the variation on some dosage, this depends on experimenter's to be treated situation.Under any circumstance, the people who is responsible for administration is by the appropriate dose determining for individual subjects.

Cyclophosphamide is 2H-1,3,2-oxa-azepine phospha cyclohexane-2-amine, and N, two (2-chloroethyl) tetrahydrochysenes of N--, 2-oxide, monohydrate; Be called Cytoxan, can be available from Mead Johnson; And Neosar, can be available from Adria.By under the catalytic action of triethylamine, in dioxane solution, make 3-amino-1-propanol and N, two (2-chloroethyl) dichlor-phosphoryl amine ((ClCH of N- ₂cH ₂) ₂n--POCl ₂) condensation, prepare cyclophosphamide.Condensation is dual, comprise hydroxyl and amino both, realize thus cyclisation.

Different with other β-chloroethyl amino alkylating agent, it is not easy to be cyclized into active ethyleneimonium form until activated by liver enzyme.Therefore, this material is stable in gastrointestinal tract, and toleration is fine, is effectively by oral and parenteral approach, and do not cause to blister in part, downright bad, phlebitis or pain even.

Comprise oral 1-5 mg/kg/ days (being generally combination) for the appropriate dose of being grown up, this depends on gastrointestinal tolerance; Or 1-2 mg/kg/ days; Intravenous, the initial broken dose of pressing 40-50 mg/kg within the time of 2-5 days, or the every 7-10 days of 10-15 mg/kg, or 3-5 mg/kg is biweekly, or 1.5-3 mg/kg/ days.Can give dosage 250 mg/kg/ days as antineoplastic agent.Due to gastrointestinal ill effect, preferably intravenous route is with input.In maintenance period, 3000-4000/mm ³numeration of leukocyte normally desired.Medicine also sometimes gives, is given or given to body cavity by infiltration through intramuscular.Can obtain the injectable dosage forms of 100,200 and 500 mg and the tablet of 25 and 50 mg.About the detailed description of dosage, technical staff can be with reference to " Remington's Pharmaceutical Sciences ", and the 15th edition, the 61st chapter, it is attached to herein as a reference.

Chlorambucil (also claiming Leukeran) is the difunctionality alkylating agent of chlormethine type, and having found has activity for particular person oncosis.Chlorambucil is chemically being called 4-(two (2-chloroethyl) amino) benzenebutanoic acid.

Can obtain chlorambucil for the tablet form of oral administration.It absorbs fast and completely from gastrointestinal tract.After 0.6-1.2 mg/kg single oral dose, in 1 hour, reach peak value blood plasma chlorambucil level, and the end half life eventually of parent drug, is estimated as 1.5 hours.Can use 0.1-0.2 mg/kg/ days or 3-6 mg/m ²/ sky or alternative 0.4 mg/kg are with antineoplaston.Therapeutic scheme is well known to those skilled in the art, and can be referring to " the Physicians Desk Reference " that quote herein and " Remington's Pharmaceutical Sciences ".

Chlorambucil is that chronic lymphatic (lymphocyte) leukemia, malignant lymphoma comprise that lymphosarcoma, giant follicular lymphoma and Hodgkin are needed in treating.It is not healing property in these diseases any, but can produce useful clinically abirritation.

Busulfan (also claiming Busulfan) is a kind of difunctionality alkylating agent.Busulfan is chemically being called Busulfan.

Busulfan is not the analog of chlormethine.Busulfan can obtain for the tablet form of oral administration.Each cut sheet contains 2 mg busulfans and non-active ingredient magnesium stearate and sodium chloride.

Busulfan is that chronic myeloid (myelocyte sample, myelocyte, granulocytic) leukemia palliative treatment is needed.Although be not healing property, busulfan reduces total granulocyte quality, alleviate the symptom of disease, and improve patient's clinical state.Approximately 90% adult who suffers from the chronic granulocytic leukemia of not receiving treatment before can obtain hematologic response, and after it uses busulfan, organomegaly is disappeared or stablizes.Show that it is better than spleen radiation with regard to life span and hemoglobin level maintain, and be equivalent to radiation controlling aspect splenomegaly.

Fluorouracil (" 5FU ") (selling using the trade mark of Adrucil, Carac, Efudex and Fluoroplex) is a kind of medicine of pyrimidine analogue as being used for the treatment of cancer.Its some main usess are colorectal carcinoma and cancer of pancreas.It is also used for the treatment of inflammatory breast cancer sometimes.

Lomustine is one of nitrosoureas being used for the treatment of some oncosis.It is 1-(the chloro-ethyl of 2-)-3-cyclohexyl-1 nitroso ureas.It is a kind of yellow powder, and empirical formula is C ₉h ₁₆clN ₃o ₂, molecular weight is 233.71.Lomustine dissolves in 10% ethanol (0.05 mg/mL) and absolute alcohol (70 mg/mL).Lomustine relatively water insoluble (<0.05 mg/mL).It is relatively unionized under physiological pH.Non-activity composition in lomustine capsule is: magnesium stearate and mannitol.

Although it is generally acknowledged that lomustine makes DNA and RNA alkylation, with other alkylating agent without cross tolerance.As other nitrosoureas, it also can be by making aminoacid carbamoylation in protein suppress the enzyme process of several keys.

Can orally give lomustine.With 30 mg/m ²-100 mg/m ²oral the giving after radioactivity lomustine of dosage range, only about half of given radioactivity within 24 hours with the form secretion of catabolite.

The scope of the serum half life of metabolite is 16 hours-2 days.After intravenous gives 15 minutes, organize level and blood plasma level suitable.

Show accepting in the patient of suitably operation and/or radiotherapy procedures, except other therapeutic modality, lomustine can be used as the single agent in constitutional and metastatic brain tumor or that established and conjoint therapy other granted chemotherapeutant.Confirm in addition, when with first therapy for treating recurrence or in the nullvalent patient of first therapy, it is effective for the secondary therapy of Hodgkin when with other granted drug regimen.

In the patient who does not receive treatment before, the recommended dose as the lomustine of single agent in adult and child is 130 mg/m ², as the single oral dose of every 6 weeks.In the impaired individuality of marrow function, dosage should be kept to every 6 weeks 100 mg/m ².In the time of lomustine and the use of other bone marrow depression drug regimen, should correspondingly adjust dosage.Understand, can use other dosage, for example 20 mg/m ², 30 mg/m ², 40 mg/m ², 50 mg/m ², 60 mg/m ², 70 mg/m ², 80 mg/m ², 90 mg/m ², 100 mg/m ², 120 mg/m ²or any dosage between these numerals, it determines to be essential to individuality to be treated by clinicist.

The another kind of standardization program of tumor and treatment of cancer in order to the operative treatment of eliminating cancer growth.This attempts to remove whole cancer growth.But operation is generally combined to guarantee to destroy any remaining tumor or malignant cell with chemotherapy and/or X-ray therapy.Therefore,, except adopting X-ray therapy and chemotherapy, also can adopt operation with treatment tumor.

Inducing DNA damage is the Main Function mode that X-ray therapy and chemotherapy are killed cancerous cell, and it also activates p53 effectively.A large amount of evidences show, the acute toxicity of DNA damage anti-cancer therapies induction mainly mediates by p53, p53, in the time activating, induces a large amount of apoptotic cell deaths in the sensitive organization including enteric epithelium, spleen, bone marrow, thymus, tongue, testis and hair follicle, causes serious pathological consequences.Consistent with these observations is to find, the cell with deficiency p53 has resistance to the apoptosis of DNA damage induction.In addition, genetics research shows, p53 deficient mice is not to being answered by the toxicity of X-ray therapy and chemotherapy-induced.P53 mediation may point out to chemotherapy and radiotherapeutic pathological reaction the potential method that suppresses p53 and can be used as improving harmful side effect, allow patient's tolerance to have more aggressive (and therefore may be more successful) therapeutic scheme.But p53 is one of most important tumor inhibitor, suppress caused potential cancer risk therefore need to overcome because of it.

P53 tumor inhibitor is to control the transcription factor that lots of genes is expressed, product mediated cell cycle arrest, DNA reparation, aging or the apoptosis of described gene.P53 is preventing that decisive role in carcinogenesis is subject to it by directly affecting the sudden change of p53 locus or the support of general inactivation in cancerous cell by the distortion of its normal regulating.Because DNA damage reaction path and carcinogenic stress pathways meet at p53, therefore think that two approach are essential for the tumor inhibitor function of p53.But up-to-date genetics research provides compellent evidence, show carcinogenic stress pathways but not DNA damage approach to be the tumor suppression of p53 mediation necessary.Use the wherein p53 state genetically engineered mouse model of reversible transformation between functional and non-activity state in vivo, shown that the DNA damage reaction of p53 mediation is irrelevant with tumor suppression, but cause the reason of pathological consequences.Strikingly find, postpone p53 and recover until acute DNA damage habituation, this keeps the protection for cancer development, and this protection depends on p19ARF.With this viewpoint (tumor suppression mediating for p53, the reaction of acute DNA damage may be optional) consistent be mice genetics research, the mutant displacement of protein kinase (ATM, ATR or the Chk2) phosphorylation that wherein endogenous p53 can not activated by DNA damage.Knock in the apoptosis that mice can not be realized DNA damage induction, but still prevent cancer development completely.These researchs show jointly, and the of short duration inhibition of p53 activity can significantly reduce the cytotoxicity of DNA damage induction and not damage tumor suppression function, and this provides studies of short duration p53 and suppress the ultimate principle as the method for the treatment of of cancer protection.

Arsenic is a kind of naturally occurring metalloid, its by by activate via the mechanism that relies on Ras-GTP enzyme nadph oxidase activity come induced oxidation stress, caused intracellular reactive oxygen species generation to break out.People, laboratory animal and cultured cells are exposed in arsenic relevant from multiple different effect.Although arsenic is fixed mankind's carcinogen, about the shape of arsenic response curve (particularly under low dosage) has very large arguement.Lack stable successful because expose induction by arsenic in animal model aspect cancer, therefore the mechanism of arsenic carcinogenesis is still unclear, and this fact makes this arguement more complicated.The epidemiological study that comprises low dosage data also shows, is exposed in the arsenic that is less than approximately 60 ppb (0.8 μ Μ) concentration in drinking water relevant with the risk of bladder cancer lower than control value or pulmonary carcinoma.But in the time absorbing with toxic level, arsenic causes serious health problem, comprises cancer.For example, in many areas of Bangladesh, the arsenic of drinking water middle and high concentration becomes special health concerns, because it improves relevant to cancer rate.But arsenic also by recommend for health is had to beneficial effect compared with under low dosage.For example, early stage to 20th century from 18th century, the inorganic arsenic preparation that is called Fowler's Solution (Fowler's Solution) (1% Potassium acid arsenate) is used to treat various diseases, comprises skin carcinoma, hypertension and arthritis.Women is even coated on skin arsenic to improve its colour of skin.Fully record the concentration associated ratings of the reaction to arsenic.For example, in adult's foreskin keratinocyte, carry out arsenite treatment at 5 μ Μ or under lower than the concentration of 5 μ Μ and within 24 hours, cause inductivity propagation, it is with nuclear Factor-Kappa Β (NF-κ Β) and the active raising of activator protein-1 (AP-1) (transcription factor of known promotion cell proliferation and cell survival).Under 10 μ Μ or higher concentration, observe cell viability statistical significance and reduce.Genome analysis shows, low dosage (5 μ Μ, no cytotoxicity) and high dose (50 μ Μ, cytotoxicity) affect the expression of almost completely free overlapping gene subclass, this is consistent to the qualitative change of short dead reaction under high dose with short survival biological respinse from low dosage, has supported to be caused by the arsenic of low concentration and high concentration the distinct character of cytosis.Stack up, obtainable information shows the two-phase dose response of arsenic; Draw by low dosage arsenic the effect that role is not only different from high dose arsenic in amplitude, and also different in nature, and cytoprotective is to cytotoxicity.

Comprise that the following example is with explanation the preferred embodiments of the invention.The technology of operational excellence in practice of the present invention that the disclosed technology in the embodiment that encloses of it will be understood by those skilled in the art that represents that the inventor finds, therefore can be considered the optimal way that is configured for its practice.But, according to present disclosure, it will be understood by a person skilled in the art that in disclosed specific embodiments and can carry out many changes, and without departing from the spirit and scope of the present invention in the situation that, still obtain same or similar result.

the arsenic of low dosage is distributed and is suppressed its activity by induction p53 kytoplasm

Cell is accumulated relevant with the of short duration processing of sodium arsenite (1-10 μ Μ continues 12 hours) of low dosage with p53 in the upper mediation of Hdm2 kytoplasm.By MAPK approach, low-level arsenite stimulates the Hdm2 of P2 promoter mediation to express, and then it promote p53 ubiquitination and the output of core subsequently.Therefore, p53 to genotoxicity stress reaction impaired, as by p53 activation when response ultraviolet radiation or the 5FU treatment with apoptosis is impaired confirms.When feed to mice containing arsenite water time, significantly weakened by the p53 dependency tissue injury of 5FU treatment induction, further confirmed that arsenite hinders the ability of p53 activation.

tumor-bearing mice protects normal structure with the arsenic pretreat of low dosage but not cancerous cell avoids chemotherapy and radiation-induced killing

In an experiment, use lung cancer cell line A549 to produce mice heteroplastic transplantation model to evaluate the effect of arsenic.Athymic nude mice (Balb c nu/nu, 4-6 week age) is purchased from Harlan laboratory.Mice is closed and supported under pathogen-free domestic condition, and remain under the cycle of 12 hours illumination/12 hour dark, arbitrarily supply food and water.By 3,000,000 cell/mices in 100 μ l final volumes, human lung cancer cell A549's (50% suspension of cell in matrigel) is subcutaneously injected into the right flank of Balb c nude mouse.When mean tumour volume reaches approximately 100 mm ³time, mice is assigned to following each group at random: contrast; Only arsenite; Only 5FU; Arsenite and 5FU; Only X-radiation; Arsenite and X-radiation.For arsenic pretreat, feed containing the water (by 1.0 mg/L) of sodium arsenite 3 days to mice.Then every daily 5FU (30mg/kg body weight) intravenous therapy 1 week of mice, or every daily 2Gy total body radiation (" TBI ") irradiates 1 week.Periodic measurement gross tumor volume.Apply following equation and calculate gross tumor volume: (volume=length x widthxhieght x 0.5236 mm ³).Also monitor body weight at whole experimental session.Numerical value is the mean value ± SE of 2 independent experiments of totally 10 mice/groups.

In solvent group or matched group, gross tumor volume is passed in time and is continued to increase (referring to Fig. 1 and Fig. 2).Arsenic treatment is to the growth of implantation tumour without any the effect that can detect, and this just shows that this of short duration arsenic treatment neither promotes tumor progression also not suppress tumor progression.The same as expected, every daily 5FU (30mg/kg body weight) is by intravenous therapy 1 week or every day causing significant tumor regression by 2Gy with the treatment of 1 week of total body radiation (TBI) irradiation treatment.It should be noted that, arsenic pretreat shows 5FU and radiation-induced tumor suppression almost do not acted on, as by 5FU or radiation-induced tumor regression with or confirm without the observed result that cannot distinguish between two groups of arsenic pretreat (Fig. 1 and Fig. 2).Therefore our data show that at least, in people's pulmonary carcinoma xenotransplantation mouse model, low dosage arsenic pretreat can not affect effect of 5FU and radiation with detecting.

Whether can protect normal structure to avoid by 5FU or radiation-induced damage in order to test low dosage arsenic in these tumor-bearing mices, the body weight that we have monitored whole experimental session changes.Monitor whole experimental session by the body weight of the mice for the treatment of described in experiment.

As shown in Figures 1 and 2, the body weight of control mice is unstable until the 7th week, slightly increases afterwards.Noticeable, arsenic treatment mice shows almost there is no body weight loss.Form sharp contrast, by its body weight of mice significantly sacrificing of 5FU or radiation therapy.This may by treatment toxicity cause because in these animals almost completely suppressed (referring to Fig. 1 and Fig. 2) of tumor growth.It should be noted that the body weight loss that has effectively stoped described treatment induction by arsenic pretreat, as the reduction of the minimum of the body weight of the mice of the arsenic-containing water of feeding confirms.

In order to organize the effect of evaluating arsenic in level, we have checked chemotherapy and the most responsive two kinds of radiotherapy have been organized to small intestinal and medullary cell.Consistent with the observed result in whole animal level, 5FU is relevant with the major injury of small intestinal and medullary cell with radiotherapy, and described damage is subject to the remarkable inhibition of low dosage arsenic pretreat.Generally speaking, result shows, the ability of not damaging 5FU and radiation destroys cancerous cell with the shor time treatment of low dosage arsenic with remarkable protection normal structure is relevant.

the persistent period of the arsenic pretreat of maximum protection is provided

Next, we have measured the persistent period of the arsenic pretreat that maximum protection can be provided.We with containing the drinking water of 1.0 mg/L arsenic to tumor-bearing mice pretreat 1,2,3,4,5,6 or 7 days.Animal is used 5FU (30mg/kg body weight) treatment 1 week every day again, and monitors body weight change.Result shows, although 1 and 2 day arsenic pretreat causes the protection lower than 3 days pretreats, is longer than the benefit of pretreat of 3 days without further increase.Stack up, our data show, for best protection, within 3 days, arsenic pretreat is seemingly enough.

it is temporary transient with reversible that the p53 of arsenic mediation suppresses

Recognize the potential cancer risk relevant with arsenic, we have checked whether the p53 of low dosage arsenic mediation suppresses is reversible.In the culture medium that contains 5 μ Μ sodium arsenite, cultivate after 3 days, by MCF10A cell, a kind of unconverted human mammary epithelial cell is in without arsenic culture medium, to recover 1,3,5,7,9 or 11 day, and evaluate the reaction of p53 to radiation.The induction that the p53 activation of radiation induction is expressed by p53 albumen abundance and p21 reflects, just can detect, and removing after arsenic almost full recovery 7 days until cell is cultivated after reaching 5 days in without arsenic culture medium.Consistent with Western blotting result, immunostaining is presented at without the core of cultivating p53 in the cell of 5 days in arsenic culture medium and distributes.Stack up, the result of cultured cell shows that it is temporary transient that the p53 of arsenic mediation suppresses, once and arsenic treatment interruption, can reverse completely.

Next we use mice to check the adjusting of the arsenic mediation of p53 activity in body.For this reason, we use peripheral blood lymphocyte reaction to radiation with monitoring p53.To feed arsenic-containing water 3 days of mice.Removing after

arsenic

1,3,5,7,9 or 11 day, from animal, collect whole blood.Lymphocyte adopts Ficoll method to separate.By described cell culture 24 hours, then with the dose irradiation of 2 Gy, and in latter 3 hours results of processing.Carry out western blot analysis.Consistent with the result of the research based on cell, recover by the p53 activation of radiation, although removing after arsenic, kinetics is slightly slower.After

radiation

0 and 1 day, the p53 of radiation induction accumulated the expression by inhibitation system with p21, recovers, and returned to untreated level at the 9th day completely the 7th day part.Generally speaking, our data show, it is temporary transient with reversible that the p53 of low dosage arsenic induction suppresses.

people's mammary gland MDA MB-231 xenotransplantation female mice

Athymic nude mice (Balb c nu/nu, 4-6 week age) is purchased from Harlan laboratory.Mice is closed and supported under pathogen-free domestic condition, and maintain under the cycle of 12 hours illumination/12 hour dark, arbitrarily supply food and water.With 3,000,000 cell/mices in the final volume of 100ml, human breast cancer cell MDA-MB-231 (50% suspension of cell in matrigel) is subcutaneously injected into the right flank of Balb c nude mouse.When mean tumour volume reaches approximately 100 mm ³time, mice is divided into following group at random: contrast; Only 5FU; Arsenite and 5FU.For arsenic pretreat, feed and carry out intraperitoneal (" IP ") pretreat (continuing 3 days in 10 μ g/ days) containing the water (by 1.0mg/L) 3 days of sodium arsenite or to mice to mice.Then mice uses 5FU (30mg/kg body weight) to treat lasting 1 week every day through i.v..Periodic measurement gross tumor volume.Apply following equation and calculate gross tumor volume: (volume=length x widthxhieght x 0.5236 mm ³).In whole experimental session monitoring body weight.Numerical value is the mean value ± SE of 2 independent experiments of totally 10 mice/groups.This experiment the results are shown in Figure 3.

The same as expected, the gross tumor volume in solvent group or matched group is passed in time and is continued to increase (Fig. 3).Treat every day and to continue to cause for 1 week significant tumor regression with 5FU (30mg/kg body weight i.v.).Arsenic pretreat shows the tumor suppression of 5FU induction almost do not acted on, as the tumor regression of inducing by 5FU with or confirm (Fig. 3) without the observed result that cannot distinguish between two groups of sodium arsenite pretreat.For the damage that checks whether low dosage arsenic can protect normal structure to avoid being caused by 5FU in these tumor-bearing mices, the body weight that we have monitored whole experimental session changes.Almost do not have the control mice of body weight loss to form sharp contrast with demonstration, with the mice display body representation work reduction of 5FU treatment.Almost stop the body weight loss of 5FU induction completely by arsenic pretreat, as the minimum reduction with arsenic trioxide pretreat Mouse Weight confirms.

human colon carcinoma xenotransplantation (5FU)

Athymic nude mice (Balb c nu/nu, 4-6 week age) is purchased from Harlan laboratory.Mice is closed and supported under pathogen-free domestic condition, and maintain under the cycle of 12 hours illumination/12 hour dark, arbitrarily supply food and water.With 3,000,000 cell/mices in the final volume of 100ml, human colon cancer cell SW-480 (50% suspension of cell in matrigel) is subcutaneously injected into the right flank of Balb c nude mouse.When mean tumour volume reaches approximately 100 mm ³time, mice is divided into following group at random: contrast; Arsenite; Only 5FU; Arsenite and 5FU.For arsenic pretreat, feed containing the water (by 1.0mg/L) of sodium arsenite 3 days to mice.Then mice uses 5FU (30mg/kg body weight) to treat lasting 1 week every day through i.v..Periodic measurement gross tumor volume.Apply following equation and calculate gross tumor volume: (volume=length x widthxhieght x 0.5236 mm ³).In whole experimental session monitoring body weight.Numerical value is the mean value ± SE of 2 independent experiments of totally 10 mice/groups.This experiment the results are shown in Figure 4.

The same as expected, gross tumor volume is passed in time and is continued to increase (Fig. 4) in solvent group or matched group.Arsenic treatment is to the growth of implantation tumour without any detectable effect, and this shows that this shor time treatment with low dosage arsenic neither causes the promotion of tumor progression is not caused to the inhibition to tumor progression yet.Treat every day and to continue to cause for 1 week significant tumor regression with 5FU (30mg/kg body weight i.v.).Arsenic pretreat shows the tumor suppression of 5FU induction almost do not acted on, as the tumor regression of inducing by 5FU with or confirm without the observed result that cannot distinguish between two groups of sodium arsenite pretreat.In the time of the treatment of response 5FU and arsenic, between male and female mice, almost there is no difference.Therefore our data show, at least, in human colon carcinoma xenotransplantation mouse model, short-term low dosage arsenic pretreat can not affect effect of 5FU with detecting.

For the damage that checks whether low dosage arsenic can protect normal structure to avoid being caused by 5FU in these tumor-bearing mices, the body weight that we have monitored whole experimental session changes.Almost do not have contrasting of body weight loss and arsenic treatment mice to form sharp contrast with demonstration, with the mice display body representation work reduction of 5FU treatment.This may be caused by treatment toxicity, because tumor almost disappears completely in these animals.It should be noted that the body weight loss that has almost stoped 5FU induction by arsenic pretreat completely, as the body weight of the male and female mice by the arsenic-containing water of feeding, minimum reduction confirms.

In order to confirm the result of measured body weight, we organize small intestinal and medullary cell by checking to the most responsive two kinds of the damage of chemotherapy-induced, are organizing the effect of having evaluated arsenic in level.Consistent with the observed result with whole animal, 5FU treatment is relevant with the major injury of small intestinal, as the significant change of the size and geometric by crypts of small intestine in both confirms.Significantly improve this damage by low dosage arsenic pretreat.The protective effect of arsenic is also obvious in bone marrow.In 5FU treatment mice, clear view arrives medullary cell exhaustion, but in arsenic pretreat mice, this reduction that medullary cell forms greatly reduces.Generally speaking, result shows, do not damage 5FU to kill the ability of cancerous cell relevant with the shor time treatment of low dosage arsenic with remarkable protection normal structure.

c57BL/6 WT and R172P knock in mice

Studies show that before us, the base mechanisms that the apoptosis of low dosage arsenic mediation suppresses is to suppress p53.Whether the mouse model that uses mutant p53 to express is mediated by p53 inactivation with the protective effect of testing viewed arsenic.Black C57BL/6 WT or the p53 R172P in age in 4-6 week knock in mice available from doctor Lazona.Mice is closed and supported under pathogen-free domestic condition, and maintain under the cycle of 12 hours illumination/12 hour dark, arbitrarily supply food and water.Mice is divided into following group at random: contrast; Only X-radiation; Arsenite and X-radiation.For arsenite pretreat, to the mice water (by 1.0mg/L) 3 days that contains arsenic trioxide of feeding.Then mice irradiates lasting 1 week with 2Gy TBI every day.In whole experimental session monitoring body weight.Numerical value is the mean value ± SE of 2 independent experiments of totally 10 mice/groups.This experiment the results are shown in Figure 5.Form contrast with wild type compatriot filial mice, in p53 Mutant Mice, arsenic provides the protection for the toxicity of 5FU induction hardly, and this has supported arsenic wherein optionally healthy normal structure to be carried out the model of protective effect by suppressing p53.

the dose dependent research of sodium arsenite pretreat

Test the sodium arsenite of 12 kinds of various dose with 6 every group male and 6 female mices.The sodium arsenite dosage self that exceeds 3500 μ g/kg body weight shows the toxicity being perfectly clear.Therefore, we have tested 7 dosage groups from 15 μ g/kg to 3500 μ g/kg.Use or do not use the arsenic pretreat mice total body radiation of 3 days with the dosage of 2 Gy.After radiation, 48 hours results animals, collect blood sample and tissue.We use p53 activity in WBC (comprising lymphocyte, macrophage and platelet) counting, GI road and GI form as a token of thing to evaluate toxicity.According to these 3 parameters, measured protectiveness arsenical weight range, it is 15 μ g/kg-1000 μ g/kg body weight simultaneously.The results are shown in Figure 6.

with the Histological research of cell after arsenic pretreat

To use the mice of sodium arsenite pretreat through receiving radiation therapy (2Gy or 6Gy) or chemotherapy (cisplatin or 5-FU), and evaluated the damage to various cells.Table 1 is presented in use or the situation without arsenate pretreat, the state of nephrocyte after chemotherapy or X-ray therapy.

Table 1

Nephrocyte

Treatment	Arsenate pretreat	Impairment scale
			w/o	Contrast	Zero
w/o	Be	Zero
			IR 2Gy	w/o	+++
IR 2Gy	Be	+
			Cisplatin, 5mg/kg	w/o	++
Cisplatin, 5mg/kg	Be	Zero
			Cisplatin, 10mg/kg	w/o	++++
Cisplatin, 10mg/kg	Be	++

Table 2 is presented at or does not use in the situation of arsenate pretreat the state of medullary cell after chemotherapy or X-ray therapy.

Table 2

Medullary cell

Treatment	Arsenate pretreat	Impairment scale
			w/o	Contrast	Zero
w/o	Be	Zero
			IR 2Gy	w/o	+++
IR 2Gy	Be	+
			IR 6Gy	w/o	++++
IR 6Gy	Be	++
			5-FU 30mg/kg	w/o	++
5-FU 30mg/kg	Be	Zero
			5-FU 50mg/kg	w/o	++++
5-FU 50mg/kg	Be	++
			Cisplatin, 5mg/kg	w/o	+
Cisplatin, 5mg/kg	Be	Zero
			Cisplatin, 10mg/kg	w/o	++++
Cisplatin, 10mg/kg	Be	++

Table 3 is presented at or does not use in the situation of arsenate pretreat the state of splenocyte after chemotherapy or X-ray therapy.

Table 3

Splenocyte

Treatment	Arsenate pretreat	Impairment scale
			w/o	Contrast	Zero
w/o	Be	Zero
			IR 4Gy	w/o	++
IR 4Gy	Be	Zero /+
			IR 6Gy	w/o	++++
IR 6Gy	Be	++
			5-FU 30mg/kg	w/o	++
5-FU 30mg/kg	Be	Zero
			Cisplatin, 5mg/kg	w/o	++
Cisplatin, 5mg/kg	Be	Zero
			Cisplatin, 10mg/kg	w/o	++++
Cisplatin, 10mg/kg	Be	++

Table 4 is presented in use or the situation without arsenate pretreat, the state of small intestine cells after chemotherapy or X-ray therapy.

Table 4

Small intestine cells

Treatment	Arsenate pretreat	Impairment scale
			w/o	Contrast	Zero
w/o	Be	Zero
			IR 6Gy	w/o	++++
IR 6Gy	Be	+
			5-FU 30mg/kg	w/o	++
5-FU 30mg/kg	Be	Zero
			5-FU 50mg/kg	w/o	++++
5-FU 50mg/kg	Be	++
			Cisplatin, 5mg/kg	w/o	++
Cisplatin, 5mg/kg	Be	Zero /+
			Cisplatin, 10mg/kg	w/o	++++
Cisplatin, 10mg/kg	Be	+++

Table 5 is presented in use or the situation without arsenate pretreat, the state of various tissues after chemotherapy or X-ray therapy.

Table 5

Tissue	Treatment	Arsenate pretreat	Impairment scale
				Kidney	w/o	Contrast	Zero
?	w/o	Be	Zero
				?	IR 2Gy	w/o	+++
?	IR 2Gy	Be	+
				Lung	w/o	Contrast	Zero
?	w/o	Be	Zero
				?	IR 2Gy	w/o	+++
?	IR 2Gy	Be	Zero
				Heart	w/o	Contrast	Zero
?	w/o	Be	Zero
				?	IR 2Gy	w/o	+/++
?	IR 2Gy	Be	Zero

the dosage conversion of zooscopy

From the data of collecting the research of mice being can be used to be identified for people's appropriate dose scope.In one embodiment, according to mice study, can using formula (1) be identified for people's dosage range:

People is equal to dosage (mg/kg)=mice dosage (mg/kg) * 0.081

If use other animal, can be by the people such as Reagan-Shaw " Dose translation from animal to human studies revisited (dosage from the research of animal the pure man of revision transforms) " The FASEB Journal, the 22nd volume, 2007, instruction in 659-661 page (it is incorporated herein by reference), according to similar formula adjusting agent weight range.

the restricted toxicity research of arsenical amount

Arsenic trioxide can obtain in aseptic injectable solution agent.Solid-state molecular formula is As ₂o ₃.Its molecular weight is 197.8 grams.Although not exclusively understand its mechanism of action, think and suppress growth and promote apoptosis in many different cancerous cell lines.For acute promyelocyte leukaemic, under the daily dose of 10 mg that IV sends in 2-3 hour in 500 ml 5% G/NS solution that use at present (consistent with the 0.15mg/kg dosage of FDA approval), blood plasma arsenic reaches average peak level 6.85 μ mol/L (scopes fast, 5.54-7.30 μ mol/L), its t1/2 α is 0.89 ± 0.29 hour, and t1/2 β is 12.13 ± 3.31 hours.Also show, give continuously the plasma concentration variation that arsenic can not cause arsenic.The metabolism of arsenic trioxide comprises and by arsenate reductase, pentavalent arsenic is reduced to trivalent arsenic and by transmethylase, trivalent arsenic methyl is turned to monomethyl arsenic acid and monomethyl arsenic acid methyl is turned to dimethyl arsinic acid.The main position of methylation reaction appears in liver.Arsenic is stored in liver, kidney, heart, lung and first.Common discharge regime is in urine.At present, there is the clinical trial in hematology and entity tumor of arsenic trioxide that many NCI support.Although arsenic trioxide is known people's carcinogen, it is extremely low-level lower always disputable to people's effect, and some of them Data support arsenic is for the protective effect of some cancer.

Evaluate for arsenic trioxide haematics toxicity, use the alternately comparison in chemotherapy cycle in the situation that does not give and give arsenic, and adopt repeated measurement design, the measurement of the effect of research to hematology's terminal.Dosage by the determined arsenic trioxide of dosage escalation is used to each patient's who acts on clinical toxicity evaluation fixed dosage.Terminal comprises hematologic parameter (numeration of leukocyte, platelet count and the hematocrit) over time of the alternate cycle of comparative chemistry therapy.Toxicity assessment only activates to its external p53 the patient who is blocked under the dosage of given arsenic trioxide to carry out.For these patients, for the

chemotherapeutic cycle

1,3 and 5, will not give arsenic trioxide.For the

cycle

2,4 and 6, will give arsenic trioxide.Before chemotherapeutic even cycle, each patient will accept the arsenic trioxide of same dose.

sum up

The induction of DNA damage is the Main Function mode that X-ray therapy and chemotherapy are killed cancerous cell, and it also activates p53 effectively.A large amount of evidences show, the acute toxicity of DNA damage anti-cancer therapies induction mainly mediates by p53, p53 is in the time of activation, and a large amount of apoptotic cell deaths in the sensitive organization of induction including enteric epithelium, spleen, bone marrow, thymus, tongue, testis and hair follicle, cause serious pathological consequences.Consistent with these observations is to find that the cell with deficiency p53 has resistance to the apoptosis of wound inducement.And genetics research shows, p53 deficient mice is not to being answered by the toxicity of X-ray therapy and chemotherapy-induced.P53 mediation may point out to chemotherapy and radiotherapeutic pathological reaction the potential method that suppresses p53 and can be used as improving harmful side effect, allow patient's tolerance to have more aggressive (and therefore may be more successful) therapeutic scheme.But p53 is one of most important tumor inhibitor, suppress caused potential cancer risk therefore need to overcome by it.

P53 tumor inhibitor is to control the transcription factor that lots of genes is expressed, product mediated cell cycle arrest, DNA reparation, aging or the apoptosis of described gene.P53 is preventing that decisive role in carcinogenesis is subject to it by directly affecting the sudden change of p53 locus or the support of general inactivation in cancerous cell by the distortion of its normal regulating.Because DNA damage reaction path and carcinogenic stress pathways meet at p53, therefore think that two approach are essential for the tumor inhibitor function of p53.But up-to-date genetics research, provides compellent evidence, show carcinogenic stress pathways but not DNA damage approach to be the tumor suppression of p53 mediation necessary.Use the wherein p53 state genetically engineered mouse model of reversible transformation between functional and non-activity state in vivo, shown that the DNA damage reaction of p53 mediation is irrelevant with tumor suppression, but form the reason of pathological consequences.Strikingly find, postpone p53 and recover until acute DNA damage habituation, this keeps the protection for cancer development, and this protection depends on p19ARF.With this viewpoint (tumor suppression mediating for p53, the reaction of acute DNA damage may be optional) consistent be mice genetics research, the mutant displacement of protein kinase (ATM, ATR or the Chk2) phosphorylation that wherein endogenous p53 can not activated by DNA damage.Knock in the apoptosis that mice can not be realized DNA damage induction, but still prevent cancer development completely.These researchs show jointly, and the of short duration inhibition of p53 activity can significantly reduce the cytotoxicity of DNA damage induction and not damage tumor suppression function, and this provides studies of short duration p53 and suppress the ultimate principle as the method for the treatment of of cancer protection.

Be not subject to the constraint of any particular theory, think the mechanism that low dosage arsenic pretreat may suppress by of short duration p53, effectively protect normal structure to avoid the pathological consequences of DNA damage induction.Importantly find, described protection is optionally for normal structure, and cancerous cell is because its deficiency p53 can not have this protective reaction.We have also set up the method that uses the impact of periphery lymphocyte monitoring arsenic on p53 activity.

the effect of low dosage arsenic to p53 in the people experimenter of embodiment-suffer from malignant tumor

The object of this research is to evaluate the activity of arsenic trioxide p53 activation in blocking-up people patient.The activation of measuring p53 by the lymphocytic external test method of patient.

method

The patient who is diagnosed as above non-leukemic malignant tumor for 18 years old is recruited in this research, and patient will start the chemotherapy of known inhibition peripheral blood counting.Expection between each cycle of chemotherapy is spaced apart minimum 2 weeks.Patient accepts the chemotherapy in the initial period that there is no arsenic pretreat, then includes the arsenic pretreat chemotherapy of the second round of continuous 3 days (during the 2nd cycle, giving arsenic trioxide at the-3 ,-2 and-1 days).Hour in treat with the dosage intravenous of 0.005 mg/kg.

By the relatively p53 activation of the 1st cycle/1st day (wherein patient neither accepts arsenic and also do not accept chemotherapy) and the p53 activation of the 2nd cycle/1st day (wherein patient accepts 3 days arsenic pretreats), measure the effect that arsenic suppresses p53.When its periphery lymphocyte does not show with 2 Gy radiation in the cultivation of the 1st cycle/1st day, the patient of derivable p53 activation is not counted in the final result of the present embodiment.

For the mensuration of p53 activation, at the approximately 10 mL whole bloods that separate in patient for the 1st day in each cycle.Then in Ficoll gradient, separate lymphocyte, cell washed with PBS, be divided into two aliquots, and before mensuration in culture medium in 37 ℃ of incubations.Next, an aliquot is exposed under 2 Gy radiation with induction p53 activation.Another aliquot does not deal with.Harvesting, cracking, is used PathScan Phospho-p53 (Ser15) Sandwich ELISA test kit (Cell Signaling, Technology, Danvers, MA) to measure the activation of p53.

Briefly, this algoscopy is to detect the solid phase Sandwich ELISA method (ELISA) of the endogenous levels of phosphoric acid-p53 (Ser15) albumen.P53 rabbit mAb is coated in micropore.With cell lysate incubation after, non-phosphoric acid-p53 albumen and the coated antibody capture of phosphoric acid-p53 albumen.After fully washing, add phosphoric acid-p53 (16G8) mice mAb to detect phosphoric acid-p53 albumen of capturing.Then use the detection antibody of the anti-mouse antibodies identification combination of HRP connection.Add HRP substrate TMB with colour developing.The amount of the optical density amplitude of described colour developing and phosphoric acid-p53 albumen is proportional.The difference of optical density between (irradiation) sample treated by checking and untreated samples, compares the activation of p53 in two kinds of samples.Optical density by the difference of optical density between treated and untreated samples divided by untreated samples, obtains percentage difference (ELISA percentage ratio).

result

Prepared group to 10 patients is studied.The patient that this analysis comprises has been defined as the patient at least one the arsenic trioxide cycle paired with the non-arsenic trioxide cycle.Derivable p53 activation when 1 people (experimenter No. 007) in described group in 10 patients is presented in the cultivation of the 1st cycle/1st day with 2 Gy radiation, this shows that this patient's lymphocyte has derivable p53.After arsenic pretreat (the 2nd cycle/1st day), when this experimenter is presented in cultivation with 2 Gy radiation, derivable p53 activation reduces.Experimenter No. 007 the results are shown in following table 6.

Table 6

This result shows, in the 1st cycle/1st day, patient shows strong p53 induction.Accepted arsenic trioxide before patient is starting the next chemotherapy cycle time, the induction of p53 is suppressed greatly.Infer and be exposed in vitro after 2Gy radiation, between the blocking-up activating at p53 in patient's periphery lymphocyte and the protection of cell survival, will approach consistent.Therefore, low dosage arsenic is useful in the method that avoids chemotherapy impact in body for the protection of people experimenter's normal structure.

In this patent, some United States Patent (USP), U.S. Patent application and other data (for example paper) give combination by reference.But only there is not the degree of conflicting by causing to be bonded between described text and other statement given in this article and accompanying drawing in the text of described United States Patent (USP), U.S. Patent application and other data.Just in case clash, any described conflict text in United States Patent (USP), U.S. Patent application and other data of the combination of described institute by reference is not attached in this patent clearly by reference.

Other of various aspects of the present invention revised and alternative embodiment will be apparent from this description to those skilled in the art.Therefore, this description should be interpreted as just illustrative, and for instructing those skilled in the art to implement the object of general fashion of the present invention.Understand, shown in this paper, should regard the example of embodiment as with the form of the present invention of describing.Replaceable key element and the material for illustrating and describe herein of key element and material, local and program can be reversed, and some feature of the present invention can be used independently, obtaining after the benefit of this description of the present invention, all these is apparent to those skilled in the art.In the case of not departing from the spirit and scope of the present invention of describing in the claims of enclosing, can modify to key element described herein.

Claims

1. a method that suppresses, prevents or reduce the damage of the non-cancerous cell to people experimenter during radiotherapy and/or chemotherapy treatment people experimenter's cancerous cell, described method comprises:

By the protective number of 1 μ g/kg/ days-125 μ g/kg/ days, need radiotherapy and/or chemotherapy to treat the people experimenter of cancer the compound of one or more arsenic, wherein before giving people experimenter by radiation and/or one or more chemotherapeutants at least 1 day, give people experimenter by the compound of one or more arsenic; With

Giving after the compound of one or more arsenic, giving people experimenter by radiation and/or one or more chemotherapeutants.

2. the process of claim 1 wherein that the compound of described one or more arsenic comprises arsenic trioxide.

3. described in the process of claim 1 wherein, the protective number of the compound of one or more arsenic is 31 μ g/kg/ days-85 μ g/kg/ days.

4. described in the process of claim 1 wherein, the protective number of the compound of one or more arsenic is 40 μ g/kg/ days-70 μ g/kg/ days.

5. the process of claim 1 wherein before giving people experimenter by radiation at least 3 days, give people experimenter by the compound of one or more arsenic.

6. the process of claim 1 wherein before giving people experimenter by radiation at least for three days on end, give people experimenter by the compound of one or more arsenic.

7. the process of claim 1 wherein the compound of one or more arsenic described in the oral people of giving experimenter.

8. the process of claim 1 wherein that intravenous gives the compound of one or more arsenic described in people experimenter.

9. the process of claim 1 wherein that described experimenter needs chemotherapy treatment.

10. the process of claim 1 wherein that described experimenter needs radiotherapy.

The method of 11. 1 kinds of chemotherapy treatment people experimenters' cancerous cell, described method comprises:

Give the compound of one or more arsenic of people experimenter;

Giving after the compound of one or more arsenic, make experimenter accept on maximum therapy can acceptable dose one or more chemotherapeutants;

Wherein on the maximum therapy that gives one or more chemotherapeutants that give after the compound of one or more arsenic, acceptable dosage is greater than the effective dose on the maximum therapy of described one or more chemotherapeutants that giving the in the situation that of lacking with one or more arsenic compound pretreats.

The method of 12. claim 11, the compound of wherein said one or more arsenic comprises arsenic trioxide.

The method of 13. claim 11, the protective number of the compound of wherein said one or more arsenic is 1 μ g/kg/ days-125 μ g/kg/ days.

The method of 14. claim 11, the protective number of the compound of wherein said one or more arsenic is 1 μ g/kg/ days-85 μ g/kg/ days.

The method of 15. claim 11, the protective number of the compound of wherein said one or more arsenic is 31 μ g/kg/ days-85 μ g/kg/ days.

The method of 16. claim 11, wherein before giving people experimenter by radiation at least 3 days, gives people experimenter by the compound of described one or more arsenic.

The method of 17. claim 11, wherein before giving people experimenter by radiation at least for three days on end, give people experimenter by the compound of one or more arsenic.

The method of 18. claim 11, on wherein said maximum therapy, acceptable dosage is determined by monitoring experimenter's CBC.

The method of 19. claim 11, on wherein said maximum therapy, acceptable dosage is determined by monitoring experimenter's body weight.

The method of 20. 1 kinds of radiotherapy people experimenters' cancerous cell, described method comprises:

Give the compound of one or more arsenic of people experimenter;

Giving after the compound of one or more arsenic, giving experimenter by radiation that can acceptable dose on maximum therapy;

Wherein on the maximum therapy that gives the radiation giving after the compound of one or more arsenic, acceptable dosage is greater than the effective dose on the maximum therapy of the radiation giving the in the situation that of lacking with one or more arsenic compound pretreats.