VINCRISTINE-INDUCED MYOCARDIAL INFARCTION EUCENM. MANDEL, MD, URILEUTINSKI, MD,

AND

MEIRDJALDETTI, MD”

A patient with lymphosarcoma treated with weekly injections of vincristine developed an acute myocardial infarction immediately after the second injection of vincristine. After he recovered from the infarction, the treatment was continued and he developed an additional myocardial infarction. I n vivo and in vitro studies have not revealed any effect of vincristine on the clotting mechanism. T h e possible causes for the association of vincristine-treated lymphoma and myocardial infarction are discussed. Cancer 36:1979-1982, 1975.

T

H E TOXIC EFFECT OF VINCRISTINE IS MAINLY

neurologic,4 manifesting as muscle weakness, paresthesia, loss of deep tendon reflexes, ptosis, diplopia, a n d hoarseness. Alopecia a n d constipation commonly occur. O t h e r rare side effects are inappropriate ADH secretion9 orthostatic hypotension,z a n d thrombocytosis.8 To the best of o u r knowledge, myocardial infarction has n o t been mentioned i n t h e literature as a complication of vincristine administration. In this study we describe n case of myocardial infarction which developed i n a patient with lymphosarcoma after vincristine administration.

CASEREPORT F.Z., a 58-year-old male originating from Rumania, was admitted to the Department because of lymphadenopathy and weakness of 1 month’s duration. Two years previously, he had suffered a myocardial infarction and since then from mild angina pectoris. On physical examination the patient was found to be in good general condition, weighing 76 kg. He had no fever. Enlarged lymph From the Department of Medicine “B,” Hasharon Hospital, Petah-Tiqva and Tel-Aviv University Medical School. Part of this work was supported by grant from the Chief Scientist Bureau, Ministry of Health, Israel. * Established Inve_stigator,Chief Scientist’s Bureau, Ministry of Healfh. Address for reprints: Professor Meir Djaldetti, Department of Medicine “B,” Hasharon Hospital, PetahTiqva, Israel. T h e authors thank Miss van-der-Lyjn for her excellent technical assistance. Received for publication March 25. 1975.

nodes, u p to 2 cm in diameter, firm, nontender, and nonadherent to skin were palpated in the neck and inguinal areas. T h e spleen and liver were not palpable. All laboratory findings, including complete blood count, renal and liver function tests were within normal limits. Electrocardiogram (ECG) on admission showed an absence of R waves in leads V,V, and Q wave in leads L,, aVF (Fig. 1). A lymph node was hiopsied and the diagnosis of lymphosarcoma was established. Treatment with weekly injections of vincristine, according to an increasing dose schedule, was started. T h e first weekly injection of 3.8 mg was tolerated well. One hour after the second intravenous injection of 7.6 mg vincristine (0.1 mg/kg body weight) the patient complained of severe pressing precordial pain radiating to the left arm which lasted for 2 hours. His blood pressure was 130/80 mm mercury, the pulse rate 100 per minute with occasional extrasystoles. An ECG recordL,, aVL, ing revealed T wave inversion in leads L, V,V,, S T depression in V,-V,, S T elevation in L,, and premature ventricular contractions (Fig. 2). Examination of blood enzyme levels showed serum creatin phosphokinase (CPK) 5.0 Menashe-Gaist units (normal 0.9-3.0 units), lactic dehydrogenase (LDH) 476 King units (normal 100-250 units), and serum glutamic oxnloacetic transaminase (SGOT) 28 Sigms units (normal 15-40 units). T h e possibility of a vincristine-induced acute myocardial infarction was considered. No reference could be found in the literature to sustain a cause and effect relationship between vincristine and myocardial infarction. Two weeks later, immediately after an ECG recording (Fig. 3), the patient was given third injection of 7.0 mg vincristine. A few hours later he complained of severe pressing precordial pain radiating to the left arm. T h e blood pressure remained unchanged, pulse rate 110 per minute

1979

CANCER December 1975

1980 9.2.

19.5.72

I

vI

?i-r--f-j . . . . ,__... ...

__-

. .

. . . . ,. . . . . . . . . . .

.

.

.:,..I,

.

.

i .

. ,

,,

. . . . . , . , ..................... ,: ., , : ...v i.,*.-I._.... i.-...i .......

-

.

.

. . . .

..

. V.

N

.

n

.

- .

. . . . . . . . . . . .- ........

.

.

V.

Vol. 36

the patient and incubated for 2 hours at 37OC with 20 ~ g / c m s vincristine. A control sample was incubated without the drug. T h e following measurements were performed after the incubation; platelet aggregation, fibrinogen concentration, factor 111, fibrin stabilizing factor, euglobulin lysis time, clotting time, clot retraction time, prothrombin time, recalcification time, kaolin-cefalin clotting time, and thromboplastin genera-tion time. No significant difference was found between the samples incubated with vincristine and those without the drug. T h e same tests performed on venous blood drawn from a cat before and after intravenous injection of 0.2 mg/kg vincristine gave similar results. Randomly bred mice, weighing 20-30 g each, were administered i.p. 0.5 mg/kg vincristine daily. After five days the mice were killed. Heart examination revealed no evidence of myocardial infarction or injury to the coronary arteries.

. i..i .. :

............

' -4+-L-k-. . . . . , .

. . . . . . . . . ......... . . .. . .. . . . . ... . - . .

t-... . . . .i.....

..

. . . - ............ .................

.,-. ~

. . ,.

V.

I

. . . . . . . . . . . . . . . . . . . . ......................

FIG. 1. Electrocardiogram taken on the day of admission. Notice the deep Q waves in lead L, and aVF, absence of R waves in leads Vl-V,, and S T depression in leads V,-V,. and regular. An ECG tracing revealed the following changes, as compared with that recorded 12 hours previously: S T elevation in leads L, aVF and S T depression in L,aVL, V2-Va (Fig. 4). Serum enzyme levels were elevated: SCOT 64 Sigma units, CPK 5.0 Menashe-Gaist units. T h e patient was kept in complete rest and the subsequent clinical course of his illness was uneventful. After recovering from the myocardial infarction, treatment with 100 mg/day cyclophosphamide and 40 mg/day prednisone gave good results; he felt well and the lymph nodes disappeared. Seven months later the patient died suddenly at home. Postmortem examination revealed lymphosarcoma involving the lymph nodes, liver, spleen, bone marrow, and small intestine. Organizing and healed myocardial infarctions of the posterior and anterior walls and the septum were found. Moderate generalized atherosclerosis of the aorta and coronary arteries was present.

Laboratory and Animal Studies Twenty-five ml of venous blood was taken from

: I_'

,

i

I,:

.........

.........

. . . . . ..... .

n

. .

. .

. .

: ,I

1.....

. . . . , .....

;

. . . . . . . . . . .

...

.

. .

I i1-

~

: .

I...;

..._

- . . .

........

_.1..

. . . .

,

ii

. . . . . . . . . . . . .

.

. . . . . . . .

.

-. J

v.

,.-*.

:

v.

r

I

FIG.2. Electrocardiogram following the second vincristine injection. Notice the T wave inversion in leads L,, L,,aVL, V,-Va, S T depression in leads V,-V,, and S T elevation in leads L.Several premature ventricular beats arc seen.

VINCRISTINE-INDUCED INFARCTION Mnndel et al. DISCUSSION

No. 6

There are several possible mechanisms for the development of myocardial infarction in a patient with lymphoma. T h e myocardial infarction could be part of the natural course of the disease. I n a large series of patients with malignant lymphoma reported by Roberts et al.,' 25% had cardiac involvement, although clinical manifestations were noted in only loo/, of these. In the case reported here, postmortem examination revealed no infiltration into the myocardium, vascular wall, o r pericardium. O u r in vitro studies did not reveal any blood clotting abnormalities after incubation with vincristine which might conceivably cause bleeding into the coronary artery wall and a subsequent myocardial infarction. T h e lack of abnormalities in the clotting mechanism found in the in vivo tests rules out the possibility that some undetermined factor, possibly vascular, is needed to cause disturbances in the clotting mechanism.

cc-

I

-..~

. . . . . . . . . . . . . . . . .

-

r

Ih

. . . . . . . Vl

. . . . . . . . . . .

,

i

-.

. . . . . . . _. .............. .- . .

.

FIG.4. Electrocardiogram taken 12 hours after the vincristine injection. Notice the marked S T depression and S T elevation in leads in leads L,aVL, V,V, L-aVF.

. .

..

. -____

........... - ..

i

.- .

.

. .

.

.

.

.

.

n

. . . . . . . . . . . . . . *...; ... , . . , . *_l___v

.. -

-

8U

F.Z.

2.1.72

1981

-

1

-

' FIG.3. Electrocardiogram taken immediately before the third vincristine iniection. Notice the T wave inversion in leads L,L,, L,aVF, and V,V,,.

I n the reported case the patient had, on two separate occasions, a n acute myocardial infarction several hours after injection of vincristine, strongly indicating a cause and effect relationship. To test this hypothesis, we injected vincristine into mice but were not able to cause myocardial infarction. There are several reports in the literature of muscular damage caused by vincristine in experimental animals.10.11 Structurally, the myofibrils do resemble the mitotic spindle and neurofibrils that vincristine is known to damage.5 Owellen" has shown that vincristine binds to tubulin, a protein subunit of microtubular structures, causing disruption and aggregation of microtubular structure in vitro. Although we could not prove either direct or indirect drug action, we presume that vincristine given at high doses did cause some change in an atherosclerotic coronary vessel or anoxic mvocarclium and DreciDitated an 1 . acute myocardial infarction.

8

CANCER December 1975

Vol. 36

REFERENCES 1. Carbone, P. P.,Bono, V., Fne, E., 111, and Brindley, C. 0.: Clinical studies with vincristine. Blood 21: 640647. 1963. 2. Cannichael, S. M., Eagleton, L.,Ayers, C. R., and Mohler, D.: Orthostatic hypotension during vincristine therapy. Arch. Intern. Med. 126290-293, 1970. 3. Cutting, H. 0.:Inappropriate secretion of antidiuretic hormone secondary to vincristine therapy. A m . J . Med. 51:269-271, 1971. 4. Johnson, I. S., Armstrong, J. G., Gorman, M., and Burnett, J. P., Jr.: The vinca alkaloids: a new class of oncolytic agents. Cancer Res. 23:139&1427, 1963. 5. Journey, L. J., Burdman, J., and George, P.: Ultrastructural studies on tissue culture cells treated with vincristine (NSC-67574)).Cancer Chemother. Rep. 52:509-!517, 1968. 6. Owellen, R. T., Owens, A. H., Jr., and Donigian, D. W.; T h e binding of vincristine: vinblastine and

colchicine to tubulin. Biochem. Biophys. Res. Comm. 47:685-691, 1972. 7. Roberts, W. C., Clancy, D. L., and DeVita, V. T.: Heart in malignant lymphoma, Hodgkin’s disease, lymphosarcoma, and mycosis fungoides. A m . J . Cardiol. 22~85-107, 1968. 8. Robertson, J. H., Crozier, E. H., and Woodend, B. E.: Vincristine-induced thrombcytosis studied with l5Se selenomethionine. Acta Haematol. 47356360, 1972. 9. Slater, L. M., Wainer, R. A., and Serpick, A. A,: Vincristine neurotoxicity with hyponatremia. Cancer 23:122-125, 1966. 10. Slotwiner, P., Song, S. K., and Anderson, P. J.: Spheromembranous degeneration of muscle induced by vincristine. Arch. Neurol. 15: 172-176, 1966. 11. Yasin, R., Hughes, B. P., and Parker, J. A.: T h e effect of vincristine on the calcium transport and phospholipid composition of rat skeletal muscle microsomes. Lab. Invest. 29:207-218, 1973.