[music] [doctor:] ...ask do we have anyguidelines for the future [narrator:] this man has acute myelogenous leukemia. he has flown from his home in denver to the u.s. public health service hospital in baltimore, for new treatment with drugs. [patient:] i didn't realize this but i wasinterested to know so that i could do some personal planning. [doctor:] yes.
[patient:] along these lines.. [doctor:] i think this is very important foryou to take care of your own, make sure your house is in order. [patient:] sure, umm i was wondering whatthe possibilities of a remission would be with the drugs which you have mentioned and how long this remission would last. [doctor:] with our present experience, we are getting remissions at somewhat over one-third, forty percent of patients. it is true that when you do reach remission status
you are clinically and hematologically normal, there's no evidence of leukemia whatsoever. now, our big problem is we are just stymied and are unable to maintain the remission too long. exactly from case to case, to predict how long it will last, i can't do. we do have some patients that have been in remission well over a year, a year and a half, two years. [patient:] that's a substantial time.
[doctor:] but there are many many patients who were only in remission one or two months. but of course, let's say we do use daunomycin, we do get a remission and in the event thatrelapse does occur, we can use cytosine arabinoside. in fact, we have other drugs after that. one of the benefits of being here at least, is that there are always new things on thehorizon that are here if a breakthrough does occur, you have a goodchance of participating
in that breakthrough here. [narrator:] in medical research, there is alwayshope for a breakthrough. can science find a drug to cure cancer? [a nurse wheels a patient on a gurney throughthe hospital.] [narrator:] cancer has been treated for sometime. many of the cancers which form solid tumorscan be treated with surgery. if all the cancerous tissue is removed, thepatient is cured. [surgeons work on a patient in the operating room.] [surgeon:] let's have another [?] please.
[narrator:] the same is true of radiationtreatments. cure depends upon destruction of all the canceroustissue. but sometimes the cancer spreads to otherparts of the body. leukemia, or cancer of the blood, is of courseall over the body. in such cases the ideal therapy would be achemical which could spread through the body and killevery cancer cell. [people are shown walking into the national institutes of health clinical center.] [narrator:] for more than a decade there hasbeen a national program to find and test anti-cancer drugs, administered and supported
in great part by the national cancer institute at bethesda, maryland. the search is worldwide. there are ten million natural products thatmight contain an anti-cancer compound. near nairobi, botanists gather leaves and the bark of trees to process and test against cancer. [botanists gather plant material.] [a man swims using a snorkel.] [narrator:] in the shallow waters of the caribbean, marine biologists collect invertebrates likethe west indian starfish. [marine biologist lifts the starfish out ofthe water.]
[narrator:] as part of the nationwide cancerchemotherapy program, they process and test the starfish to findout whether it might contain drug materials effective against leukemiasand solid tumors. the search goes on in north carolina, with the gathering of plants and grasses by botanists with the united states departmentof agriculture. [the botanist digs plants out of the soil.] [narrator:] any of these could contain a valuableanti-cancer agent. to test these materials for anti-cancer activity,
researchers might screen them in one thousandanimal tumors... against one hundred different human cancers. how can scientists determine what chemicalsare in these dried twigs? [scientist prepares twigs to be crushed and analyzed.] [narrator:] how can such chemicals be testedsafely in human beings with cancer? the unknown material sent in from the field is first processed and tested for anti-cancercapability in two so-called animal models: laboratory mice, with a known leukemia, andrats with a known tumor.
[scientist injects animals.] [narrator:] these two types of cancer catchalmost all actives. if the compound is an active, it will reducethe tumor mass, as compared with the tumor in a rat that gotno compound. [the tumors are placed side by side to compare the effects of the two treatments.] [narrator:] but if the compound kills tumor cells in a rat, it is likely to kill some normal cells too. to measure these adverse effects, researchers administer the compound to monkeys.
[a monkey is injected.] [narrator:] after a suitable period, they removea sample of the monkey's blood and subject it to a series of tests that reveal the effects of the unknown chemical on normalblood cells. for example, the coagulation time. [doctors use a stopwatch to monitor the coagulationtime of the monkey's blood.] [narrator:] other tests show other effectson the blood, and on the kidney, the liver and spleen, and particularly on the bone marrow
where red corpuscles and white blood cellsare manufactured. such tests indicate the chemicals' toxicity and help define a safe dose for the testin human beings. if a compound shows anti-cancer activity, other researchers try to determine what itis composed of, by means of column chromatography and many other tests. the chemical compounds flowing down this column, stratified in this way because of their uniquemolecular properties, may turn out to be potent anti-cancer agents.
more likely they will not. only about one agent in fifteen thousand testedhas proven effective. chemists also attempt to synthesize new anti-cancer agents. this is a plastic model, enlarged thousandsof times, of a molecule essential to the reproductiveprocess in all cells. to produce one effective drug, researchers over many months removed one ofthe hydrogens and put a fluorine in its place, producing an antagonist that is absorbed by the cell
as if it were the real thing... then destroys it. in the last test, a safe and effective dose for human beings is determined by preclinical pharmacologists. [researchers in white lab coats enter a meetingroom.] [narrator:] the moment of truth in the longsearch is the clinical trial. will the leaves and grasses from nairobi, or the compound synthesized in a laboratory,
make a drug to control cancer in human beings? this is a regular staff conference in theclinical center at bethesda. case histories of patients on trial programsare presented. in this instance, the first patient on a newdrug. then the doctors discuss the implicationsof their findings for the nationwide research program. [muffled noise from doctors chatting in thebackground.] [narrator:] a doctor wonders where the firstphase of drug study should be done. [clinical doctor 1:] in other words, maybethe phase one study
should be done on patients with diseases in which there is no established, accepted therapy that would benefitthem. [clinical doctor 2:] suppose you get phaseone information, say on a solid tumor, and you get some idea what the toxicity, but you really, is that going to apply inthe face of an acute leukemia, cml [?] and i, i think.. [clinical doctor 1:] well, at least you wouldhave evaluated the drug under uh, relatively clean conditions. [clinical doctor 3:] yeah but i think theproblem...
[clinical doctor 1:] where it gets complicatedi think, when it involves the marrow, the disease involvesthe marrow. [narrator:] much research is being done onthe size of the dose. large single doses kill cancer cells effectively, but they also kill some normal cells, so doctorsmust balance dosage against adverse side effects. [clinical doctor 2:] chuck, we've had one patient who's been on eight hundred, which is twice this dose. [chuck:] and what's happened to him?
[clinical doctor 4:] uh, he tolerated thesingle dose of eight hundred milligrams [?] quite well. he left the hospital. the second set of liver function tests aregoing to be done this week. uh, but uh we haven't heard from him. i venture he's doing quite well. [narrator:] combinations of four drugs areeffective, but it has been difficult to follow up certainfour-drug programs with some of the new drugs, such as cytosinearabinoside. [clinical doctor 1:] i think this brings upan important point
about where phase one studies should be done, because we noted when we first started usingcytosine arabinoside, it was after the four-drug combination, afterpeople relapsed, and we saw a significant number of patientswith uh, often quite severe lymphatic damage with cytosinearabinoside. and we were very concerned about it. other institutions were starting right offwith cytosine arabinoside, and you know, and so i think it's probably for the samereason. the people we had had been in remission anaverage of nine or ten months.
and uh, the time they got the cytosine arabinosidethey were just more sensitive to drugs. same thing applies to re-induction with thefour-drug combination. we saw a higher degree of lymphatic dysfunctionin re-induction with the same drugs than we did in primary induction when the patient was first diagnosed. [muffled noise in the background; doctorschatting again.] [narrator:] some cancers adversely affectthe bone marrow, where red corpuscles and white blood cellsare produced. by studying a sample of the bone marrow,
doctors can follow the evolution of the disease and the effects of different drug programs. [clinical doctor 2:] what does the presentbone marrow show? i mean, did we get our own marrow or are we relying on the marrow from cytogenetics? [off-screen doctor:] no, we have not obtainedthe marrow yet. [female doctor:] he hasn't had one yet here, but he had [?] rods in the peripheral blood so we're not in any doubt about the diagnosis.
[off-screen doctor:] but the percent blastsare only five percent. [narrator:] to take a marrow sample, the doctorcarefully anesthetizes the local area, then inserts the needle through the fleshinto the end of the bone. [a needle is inserted into the bone of thepatient.] [the needle is forced further down until itreaches the bone marrow.] [narrator:] and on into the marrow. a syringe withdraws a small sample of themarrow. this is placed on microscope slides, thenexamined. [the slides are prepared and placed under a microscope., which the scientist adjusts.]
[narrator:] this marrow sample from a patientwith acute leukemia is hypercellular, saturated with malignant cells. at a larger magnification the malignant cells, called blasts, show an unusually large nucleus. after two courses of treatment with drugs, a marrow sample might show fewer blasts and increasing numbers of normal white cells,a sign of improvement. later, in remission, when the disease is undercontrol, there will be only five percent blasts.
but the peripheral blood, the blood that isflowing through the body, is also a good indicator of the state of the patient's disease and the efficacy of treatment. [narrator:] a sample of the patient's bloodis diluted and placed on a counter. the dials reveal the number of blood cellsin a measured sample. a symptom of leukemia is an excessive numberof abnormal white blood cells, ineffective against invading micro-organisms. cancer research needs many blood donors. [a woman sits in a chair, having her blood drawn by a medical worker.]
[narrator:] leukemia, for example, sometimesreduces the number of blood platelets, the tiny cells that maintain the integrityof blood vessel walls, bleeding may result. but, platelets can be replaced by transfusion. whole blood is removed, centrifuged to bring down the heavier redcells, and placed on an extractor that squeezes the platelet-rich plasma off the top of the sample, for transfusion intothe patient-- in this case, the son of the donor.
since both the drug and the cancer may affectthe body's ability to resist invading micro-organisms, many patients die of infection. for protection, some patients are placed ina plastic bubble that completely surrounds them at all times. doctors conduct routine examinations even though they are completely cut off fromthe patient. only filtered air and aseptic materials enterthis sterile, private world. yet doctors can perform bone marrow and otheroperations.
[doctor extracts bone marrow from the quarantinedpatient.] [narrator:] this laminar flow room now undertest at bethesda may someday replace the plastic bubble. it will repel micro-organisms by continuallyblowing fresh, filtered air across the patient. doctors and visitors will enter and remaindownstream if the experimental drug cannot control thenumber of white blood cells, doctors use the continuous-flow blood cellseparator, shown at the m.d. anderson hospital and tumorinstitute in houston.
the machine draws whole blood from one arm, pumps it through carefully sterilized tubesto a weight-sensitive buffer bag which controls the pump, and sends it to a centrifuge which is similarto a cream separator. because of the different densities of whitecells, red cells, and other blood elements, they separate at different points along theradius of the disk. unwanted cells are shunted aside and the restreturned to the patient. [chuck:] this is an important point...
[narrator:] if a drug is successful againstone kind of cancer in phase one, it is tested against other kinds. then it is sent for further tests to manyhospitals around the country. [clinical doctor 2:] does anyone know what the liver toxicity has been with the first end result? since that's been tried pretty extensively now in the midwest. [clinical doctor 1:] there has not reallybeen much mention made of liver toxicity in the patients that have beenevaluated after therapy, so i would assume, although i don't know directly, that we haven'tused the old drug here.
that there really isn't a significant amountof liver toxicity with that particular kind of thing. [narrator:] always there are the questionsof scheduling. balancing dosage against toxicity. [clinical doctor 1:] we ought to really becareful about how we evaluate and look at toxicity... [clinical doctor 2:] no [clinical doctor 1:] in the circumstancesthat occur so we don't do this all over again. [clinical doctor 2:] i'll agree with you verymuch on that. the thing is, one of the reasons that we arehappy with this
type of schedule; that is, giving one dose, and then waiting to see recovery, is that it gives us time to back off and letthings uh, let the toxicity abate, and i think it's probably the safest way tostart out giving a drug. [narrator:] and finally the question of anadequate trial for each drug. [clinical doctor 3:] what would you consideran adequate trial for this drug, how much and how long? [clinical doctor 1:] in this particular patient?
[clinical doctor 3:] yes, how long? [clinical doctor 1:] well, i think that the,i would think that in this particular patient, if the physicians in charge think it's dueto liver, then i suspect...liver toxicity is due tothe drug... then you can say well, we have this stuffbecause of liver toxicity, but my only question is i'm not so sure wecan attribute it all to the drug and would feel that the risk involved in givinghim, say, a half-dose would not be that great.
it would still allow us to see if this drugis indeed going to be useful. and we're hoping that uh, this drug wouldbe useful in this particular instance. [narrator:] in clinical research the doctoris concerned not just with a drug and an effective scheduleof administration, but with a whole patient and his disease. [doctor:] you've given her daunomycin how long? [doctor 2:] she's gotten one dose. [doctor:] one dose. [doctor 2:] exactly one week ago and she isscheduled for her second dose today.
[doctor:] have you ever had any trouble withyour heart? [patient:] not that i know of. [doctor:] never had a murmur as a child? [doctor:] have you found anything? [doctor 2:] her cardiac status is completelynormal as far as we can tell. [narrator:] but the doctor always returnsto the key questions. which dosage has worked? which schedule hasbeen most effective? [doctor 2:] a level of sixteen thousand ortwenty-five thousand, but in terms of concentration, it's not toodifferent.
[doctor:] she didn't respond at all to actinomycin? [doctor 2:] ahhh, on one occasion her titer became completely negative, that is zero, and subsequently came back upagain, though. this was on actinomycin day. [doctor 2:] in the last few months she's received three or four courses of methotrexate infusiontype and her titers have gone down and back up, but her general course has remained essentially unchanged. [doctor 2:] in the light of the natural course of this disease it's fair to say the methotrexate has beensomewhat effective.
[doctor:] did you ever decide in your mindwhether she was really drug-resistant or just perhaps a dosage...schedule... [doctor 2:] i think it's difficult to say. if we could give the methotrexate more often,perhaps we might have a better effect. [doctor:] what's been the limiting factor... [doctor 2:] the limiting factor has been um,toxicity related primarily to the ulcerations in her mouth and uh, which have been quite severe, although not complicated by infection so far. [doctor:] she had ulcerations anywhere elsewith methotrexate?
[doctor 2:] no, not that we know of. [patient:] a rash. [doctor 2:] she did have a rash on her skin, which i couldn't say was clearly related tomethotrexate, but may have been. she has not had it with each dose. [doctor 2:] she's tolerated therapy actuallyquite well. [doctor:] did you notice anything when yougot your first dose of daunomycin? [patient:] no, i was really surprised. [doctor:] pleasantly surprised?
[patient:] yes, very much so. [doctor:] well, it's going to be a long dosageschedule. [patient:] okay. [doctor:] we've had some good luck with it,as dr. nigel mentioned. [scene switches to a different patient's room.] [doctor 1:] good morning. [mr. simpson:] good morning. [doctor 1:] how are you doing today? [narrator:] the guiding principal in all goodclinical research
is concern for the patient. [doctor 2:] that's not a worry, we don't, we're not quite as relaxed as you are. [patient:] boy, i'm not relaxed. [doctor 2:] how's the back doing today, andthe legs? [mr. simpson:] my legs hurt. [doctor 2:] they do hurt. [mr. simpson:] down here yeah. my back don'tbother me, hasn't for a long time. [doctor 2:] i wonder if you could roll overon your side, and roll towards the window. we just want to feel your back.
[patient turns toward the window as instructed and doctor places his hand on the man's back.] [doctor 2:] i want you to tell me, mr. simpson if this uh, when and if this hurts you at all. that tender? [mr. simpson:] no, not yet. [doctor 2:] that tender? [mr. simpson:] nope. [mr. simpson:] that's a little bit. [doctor 2:] how 'bout over here?
[doctor 2:] over here? [mr. simpson:] no. [doctor 2:] right here? [mr. simpson:] well, i believe that's a littlebit right there. [doctor 2:] here? [mr. simpson:] no...a little bit right there. that's it at the end of your finger. right there. [doctor 2:] a lot or a little bit? [mr. simpson:] no, just a little.
[doctor 3:] i wonder if the [?] would reproduce any of the pain down the leg. well, tom, we finally got the results on the x-rays. [mr. simpson:] and what'd you get? [doctor 3:] and there does seem to be something that may well be causing the pain downthe leg, but it's in this area. uh, we're going to talk with the radiotherapypeople today and see if they can help us on it. we'll let your know later on today on that. [mr. simpson:] you'll let me know today.
[doctor 3:] i think so, it'll depend on whenthey will be able to get to see you. your next course of chemotherapy starts nextweek. [mr. simpson:] next week? [doctor 3:] yeah, tuesday.. [doctors 1 and 3:] monday or tuesday [doctor 3:] depending on what your blood countshows. they think they can help you if they combinethe two. [mr. simpson:] okay. [doctor 3:] okay so maybe that's, that's what'sdoing it.
[mr. simpson:] you think so? [doctor 3:] yeah, i think. [doctor 2:] pretty good chance, uh-huh. [mr. simpson:] i think that sounds right. [doctor 2:] well everything else, you know,has improved. lump has gone down, chest is better and soforth. [doctor 2:] so if we can get this pain undercontrol i think uh, everything should be a lot better, mr. simpson. [doctor 2:] so that's what we're shootingfor.
[mr. simpson:] all right. [doctor 2:] okay. [narrator:] where has the national cancerinstitute program led? in advanced forms of hodgkin's disease, a four-drug treatment produced complete remissions, or temporary disappearance of all evidence of cancer in twice as many patients as ordinarily achieved remission with singledrugs. a group of thirty-five children with acuteleukemia were treated intermittedly with massive doses of four drugs.
the median survival of these children wasthree years compared with a three-month survival of leukemicchildren twenty years ago. the story of cancer drug research will continuenext week in part two, "the battle in the cell." [narrator:] for further information on cancer chemotherapy, write for a free booklet, drugs versus cancer, available from the research information branch, national cancer institute, bethesda, maryland. [narrator:] these are normal human cells from prostatic tissue
living in a laboratory dish. they were filmed through a microscope that magnifies them two-hundred seventy times. these are the same kind of human cells fromprostatic tissue, grown and filmed in the same way, but they are cancer cells. the cells, normal and cancer, differ in waysnot yet fully understood. it is the task of the cancer chemotherapist, the scientist who hopes to control cancerthrough the use of drugs,
to exploit those differences so that a drug can kill all of these cells, without killing more than a few of these in the same human being. [narrator:] cancer has been treated successfully for some time by surgery in which the malignant tissue is removed. and by radiation in which it is destroyedby cobalt and x-rays. but sometimes cancer spreads to other parts of the body even as the local area is being treated successfully. in such cases, new hope may be offered by chemotherapy, the use of drugs.
[doctor:] what treatments have you had? i know you had surgery; did you ever have x-ray therapy? [patient:] um-hmm [doctor:] when was that? [patient:] sixty-three i think. couldn't sayfor sure. [doctor:] and that was for a local recurrenceof your disease, i think. [patient:] yes. and then, did that hold it under control for a little while? [patient:] yes, it did. [doctor:] and then what happened?
[patient:] well then, it started all overagain. [doctor:] have you ever received any othertherapy? uhh, very often patients with breast cancer get estrogen therapy, corticosteroids, cortisone. [patient:] the only thing i had was thosepills. and what are those, i can't pronounce.. [doctor:] diethyl silbesterol, that's it. [doctor:] these are, are pills, this is hormones that very often control cancer, breast cancer.
did this help? [patient:] yes, when i was taking two or three it helped make it better. then i had to stop because i had started my period. [doctor:] basically, the problem with your disease is that you did have localized disease and you received surgery and then for a local recurrence, radiotherapy, and i think now the problem is that the diseaseis just too far out, too widespread to be controlled by any of these local means.
[doctor:] where did dr. hunter tell you thatyou had disease? [patient:] my breast. [doctor:] eventually what happens in canceris that we do have to use drugs. [patient:] mhmm. [doctor:] even after local therapy and afterhormonal therapy. you did have the hormonal therapy, and the disease has progressed to the point where your doctor did feel thatyou should go to a center that is more concerned, that has more experiencein drug treatment. [patient:] right.
[doctor:] were you happy about going or wereyou, how did this strike you when you discussedthis with him? [patient:] well, it kind of shocked me a little bit. then i made up my mind i would, he, he advisedme it was the best thing for me to do. he said that if i could get in here i would be very lucky, so i told him i would. [narrator:] for more than a decade, the national cancer institute has guided and supported a large national program of cancer chemotherapy. scientists are studying the whole patient, the effects of many kinds of drugs on thecourse of his disease,
and on the inner workings of cancer cells. a cell is visible to the human eye only througha microscope. nevertheless, it is the building block ofwhich all tissue is made. when new tissue is needed the cell divides, each so-called mother producing two daughters exactly likethe mother. each daughter produces two more daughters,also the same. when no more tissue is needed, the doublingstops, halted by an unknown biological signal. the cancer cell and all its daughter cellsdo not receive
or do not obey the signal. they keep multiplying far beyond what thebody can tolerate. this relentless growth of nonfunctional cellscan lead to illness and death. the experimental evidence of this is startling. blood is withdrawn from the abdomen of a mousewith leukemia. [scientist uses a syringe to to withdraw blood from the mouse's body.] [narrator:] it is diluted. and the cells are counted under a microscope. they are diluted and counted again,
until any given drop is likely to containonly one or two leukemic cells. with this instrument, called a micro-manipulator, scientists at southern research institute in birmingham today can isolate a single living leukemiccell. [the scientist assembles his micro-manipulator.] [narrator:] using a hair-like tube, the technician places several drops of the diluted material on a glass slide. the slide is turned over so the drops are hanging from the lower surface, and is placed under a microscope.
the technician locates a single drop. he carefully moves a pipette, a delicate glasstube, up under the slide. and with hydraulically-operated controls thatscale down his movements, he inserts it into the droplet... and withdraws the leukemic cell. the cell is transferred to a hypodermic syringe. a single cancer cell. it is injected into a normal, healthy mouse. [a researcher holds a mouse in her hand and injects the cancer cell, then places the mouse in a cage.]
[narrator:] within eight days, there is anoticeable abdominal swelling, evidence of the growth of leukemic cells. the cancer cells continue to increase, eachmother producing two daughters. each daughter producing two more daughters. until, after ten days the swelling in theabdomen is pronounced. by the nineteenth day, the single cancer cell will have proliferated to more than one billion cells. enough to kill the animal. but certain chemicals can stop this cancerousgrowth.
in this laboratory culture, we see mouse leukemia cells dividing, with cleavage as shown in the center of the screen, completed after the usual length of time. but when a drug is added, the reproductive cycle of the cells is violentlydisrupted. the cell in the center of the culture staysat metaphase, an intermediate stage in the division process, an unusually long time. cleavage is irregular.
daughter cells are of unusual size and do not survive very long. human cancer cells are also affected by drugs. these cancer cells in a laboratory dish are dividing in the usual way, as shown at far right. if an alkaloid from the periwinkle plant is added, cells proceed to the second phase of the cycle, as seen in the rounded cells, but cannot go beyond this phase. mother cells cannot produce daughters,
stopping the relentless reproduction that characterizes the growth of cancer cells. but it has been found that a given dose ofa given anti-cancer drug destroys only a certain percentage of thecells in a living animal. regardless of the absolute number of cancer cells, the percentage destroyed by the same size dose will always be the same. suppose a given type of cancer cell doublesapproximately every twelve hours. once every twenty-four hours we administera drug
which kills sixty percent of the cancer cellspresent. again, the remaining cancer cells double. and again, we kill sixty percent. we have slowed them down, but they are increasing faster than we arekilling them, and they will eventually increase in massor number to the point where they kill the animal. we can increase the doses so that we are killing the cancer cells fasterthan they can multiply.
but anti-cancer agents also affect normalcells. if the dose is too large, and if too many normal cells are killed whilewe are destroying the cancer cells the animal may sicken and die. is it possible to kill large numbers of cancercells with drugs without killing too many normal cells? [narrator:] these normal mice are injectedwith an anti-cancer drug called cyclophosphamide. twenty-four hours later the femur, or upperleg bone of the mouse, is removed, the ends clipped,
[the scientist uses a tiny instrument to clips the ends of the mouse's femur bone.] [narrator:] and the bone marrow, the siteof blood-forming stem cells, is washed out and diluted in a laboratorysolution. [the described procedure is shown.] [narrator:] to find out how the drug has affectedthe marrow and its ability to produce cells, the technician injects the diluted marrowinto a mouse whose stem cells have been destroyed. ten days later, after the injected marrowcells have had a chance to multiply,
the animal's spleen is removed and fixed inbouin solution. [the mouse's spleen is dropped into a testtube filled with the solution.] [narrator:] marrow cells form nodules on the spleen. the number of nodules, in this case a dozen or so, indicates the number of cells surviving, a measure of the effects of the original anti-cancer agent on the normal cell. but what does the agent do to cancer cells? a lymphoma-bearing mouse is injected and twenty-four hours later its bone marrow is removed.
again following the same procedure used with the normal mouse, the marrow is diluted and injected into the tail of a mouse, which will serve as a kind of incubator or culture dish for the marrow cells. eight days later the spleen of the cancermouse is removed. again the nodules are counted, an indication this time of the rate of survival of cancer cells after drug treatment. to get good data, sixty-six such experimentswere conducted
at the ontario cancer institute, each one involving more than one hundred mice. when the results were plotted, the curve showing the percent survival of normal cells as against increasing drug dosage, looked like this. [man draws curve on paper indicating relationshipbetween dosage and cells killed.] the curve indicating percent survival of cancer cells with increased drug dosage looked like this. there is no question that some drugs killmany more cancer cells
than normal cells in the same living organism. and that kill-ratios vary with dosage. so, dose amount, as well as timing, is important in the battle in the cell. but can we further improve this ratio? the ratio of cancer cell killed to normalcell killed. just within the past couple of years, a new approach to this problem has been developed, based upon close observation of the life cycleof the cell. in addition to the phase during which thecell divides,
there are several other cycle phases. generally, cells appear to rest in one phase, synthesize genetic material in another, rest again, then divide. [a graphic illustrates as narrator describes the process.] but timing is crucial. how can we find the length of each phase inthe life cycle of a cancer cell? at southern research institute, researchers use a radioactive material thatis absorbed into cancer cells
during the s phase. [scientists move about in the lab, preparing to run a test on the lab mice.] they inject it into laboratory mice with the solid tumor designated sarcoma 180, let the tumor grow, then remove it. in this tumor, how many cells have taken upthe radioactive material? how many have passed through the s phase andon into mitosis, or cell division? [the scientist is shown cutting a tumor in a petri dish into small pieces.]
after mincing the tumor, the technician suspends it in a measured amountof saline solution and carefully breaks down the tumor tissuein a laboratory homogenizer. [a whirring sound is heard as the described process is shown.] then the technician strains the mixture to remove large clumps of tissue, and places the liquid containing radioactivecancer cells into a centrifruge. [the centrifruge begins spinning.]
later, the packed cells are treated in other ways and are placed on glass slides, each carefully marked for future identification. [carrying the cell sample slides, a scientist approaches and opens a lab door marked "warning."] [narrator:] to find out how many cells areradioactive, and thus have passed through the s phase, the slide is converted into a kind of photographicplate. it is coated with emulsion and left in a darkroom for six weeks. [the described process is shown.]
to count the cells that have absorbed theradioactive material, the researcher not only examines all portions of the slide under a microscope, but also studies it on closed-circuit television. cells containing radioactive material are identified by the dark spots on the emulsion. on this slide, over three thousand cells werestudied and counted. from this experiment, the researchers determined that the life cycleof the sarcoma 180 cell
is about thirteen and a half hours, and that the s phase lasts almost eight hours, important data in determining the best time to administer drugs that kill during the sphase. of the thousands of drugs tested, some apparentlykill only during the s phase of the life cycle. yet their kill ratio is good. of the thousands tested, some were found tokill throughout the life cycle and they also can give good cancer-cell tonormal-cell kill ratios. but when these different kinds of drugs arecombined,
they can give much better kill ratios. much experimentation involves drug schedules. experimenters at southern research institute have developed ways to administer drugs steadily, over long periods of time, to mice with different kinds of cancer. a tube is inserted intraperitoneally and the mouse is allowed to run into his smallchamber along with a dozen or so of his cousins. the experimental drug is drawn into a specialsyringe.
and the syringe is mounted on a rack, one syringe for each mouse. other syringes are filled with harmless salinesolution for administration to a group of control mice. they will be watched to see whether the apparatus,rather than the drug, affects them in any way. now each syringe is adjusted precisely to ensure administration of a carefully measuredamount of drug. the mice in their stalls are given a finalcheck,
a timer is started, and the drug is fed through the tubes at a constant rate. in this apparatus, the drug can be made eventuallyto hit every cell in a cancer mass, no matter when or how long it is susceptibleto the drug. but scientists thought it might be betterto treat the animal with a single, stronger dose, followed by other doses at a later time, perhaps giving the normal cells more timeto recover
from drug damage before they are treated again. not long ago, southern research institutetested cytosine arabinoside in a batch of mice with leukemia. [a researcher makes notes on a pad of paper.] in the first experiment, they gave a measured dose of drug to hundredsof animals, once each day for a period of fifteen days. some mice were used as controls; they got no drug.
at the end of the experiment, the control mice died, as predicted on the basis of the growing knowledgeof cell kinetics. the experimental mice, those that got the drug, lived much longer, although all eventually died. when the results were averaged out, it wasdetermined that the daily dosage had increased the lifespan of the experimental mice substantially, although none were cured. but, by simply changing the timing of theadministration, the scientists got dramatically differentresults.
they used the same kind of mice, mice which have been inbred for generations to enhance their similarity for laboratory purposes. and the same drug, cytosine arabinoside, and essentially the same size dose. but instead of administering the drug oncea day, they administered it every three hours aroundthe clock, at four-day intervals. control mice again got no drug,
and again they died according to estimatesbased on cell kinetics. the experimental mice, those that got thedrug on the new schedule, continued to live happily. some laboratory animals can be cured of cancer, but human beings are a far cry from laboratoryanimals. can drugs be found or designed that will destroythe billions of cancer cells that sometimes spread through human beings? [a person enters a number using a rotary dialpadon a large computer.] a computer program developed at the nationalcancer institute may help find the answer.
into the computer are fed assumptions about the generation time of a given cancer cell, the duration of the s phase, and the fractional cell kill of a given drug. in seconds, the computer can reveal, amongother things, the number of cells remaining at the end ofthe dose period. with such information, drug programs can betailored for individual patients. other progress is being made. the animal model for testing drug activityagainst cancer
is giving good biological information that has a direct bearing on the disease inman. although enormous problems remain, there is hope that continued research will lead to even greater life expectancyfor even more patients. [narrator:] for further information on cancer chemotherapy, write for a free booklet,
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