[CANCER RESEARCH 50. 3473-3486. June I5. I990]
`
`Review
`
`
`
`Antineoplastic Activity of the Combination of Interferon and Cytotoxic Agents
`
`against Experimental and Human Malignancies: A Review'
`
`Scott Wndler2 and Edward L. Schwartz
`Department ofOncology, Albert Einstein Cancer Center. Montefiore Medical Center. Bronx. New York 1046?
`
`Abstract
`
`The combination of interferon (IFN) and conventional chemotherapeu-
`tic agents offers a promising therapeutic approach for the treatment of
`cancer. However, there is as yet no consensus on optimal strategies for
`combining this family of compounds with other cancer therapies. While
`in vitro studies have demonstrated both direct cytotoxic and cytolrinetic
`effects for IFN, a more interesting role derives from its ability to
`synergistic-ally potentiate the activity of a wide variety of cytotoxic agents
`against multiple human and rodent tumors. both in vitro and in animal
`models. The interaction between IFN and cytotoxic agents in vitro is
`complex and depends not only on the choice of cytotoxic agent but also
`on the concentrations, ratios, duration, and sequence of exposure to the
`two drugs. Preliminary data suggest that some combinations are not
`merely additive but rather that IFN may biochemically modulate the
`cellular uptake or metabolism of the cytotoxic agent resulting in syner-
`gistic antineoplastic activity. In rim interactions between IFN and cyto-
`toxic agents involve an additional layer of complexity because of the
`potential effects of the biolofical agent on the host immune system and
`drug-metabolizing enzymes. Furthermore, IFN may have a protective
`effect on normal host tissues which theoretically could allow for the
`delivery of higher doses of cytotoxic agents. The results of early clinical
`trials using combinations of IFN with chemotherapeutic agents have
`generally been disappointing. This may be due to the inability of preclin-
`ical models to accurately predict the clinical situation or alternatively
`from a failure to incorponle lnfornntion on dose, scheduling, and se-
`quence of drug administration into clinical trials. Preliminary clinical
`studies with IFN-a and the fluorinated pyrimidine, S—fluorouracil, in
`patients with advanced colorectal carcinoma suggest that IFN may en-
`hance the effects of the antimetabolite. Confirmatory trials are in prog-
`ress. Further trials designed to exploit the preclinical experience with
`combinations of IFN and cytotoxic agents are warranted.
`
`Introduction
`
`Combination chemotherapy has a recognized role in the cure
`of such disseminated neoplasms as testicular cancer,
`lym-
`phoma, Hodgkin’s disease, and acute leukemia. A standard
`strategy for the design of regimens containing multiple cyto-
`toxic agents is based on the following premises: the drugs used
`have direct actions on the tumor cells, with some selectivity
`compared to normal cells {1); efficacy is likely directly corre-
`lated with the intensity and duration of drug exposure. and
`therefore drugs should be used at or near their maximal toler-
`ated dose (2); optimal combinations utilize agents with different
`mechanisms of action (3); and drug combinations should be
`selected to minimize any overlapping toxicities of the individual
`
`drugs (4). The incorporation of biological agents, often termed
`biological response modifiers, into combination regimens with
`standard chemotherapeutic agents offers an important chal-
`lenge to the medical oncologist since the assumptions for their
`use likely differ from those for chemotherapeutic agents. These
`agents. which include the interferons, the interleukins, tumor
`necrosis factor and other cytokines, and colony-stimulating and
`other growth factors, have diverse physiological actions and
`interactions. Factors impeding the development of rational
`strategies for incorporation of these cempounds into clinical
`regimens include: (a) their poorly understood mechanism of
`action (5); (it) their relatively weak or absent cytotoxic activities
`(6}; (c) a novel spectrum of toxicities (7); (d) a wide range of
`biologically effective doses (8}: and (e) the absence of a clear
`correlation between maximum tolerated dose and optimal ther-
`apeutic effect {9). Thus, it is far from clear what the optimal
`strategy for combining cytotoxic agents and biologics might be.
`The lFNs’ are a family of naturally occur-ring glycoproteins
`which share antiviral, immunomodulatory, and antiproliferative
`effects. Discovered in 1925'}r by Isaacs and Lindenmann (10),
`their antitumor activity has been the most thoroughly studied
`of the biological response modifiers. Early clinical trials estab—
`lished activity for lFNs as single agents against two relatively
`uncommon malignancies, hairy cell leukemia and acquired im-
`munodeficiency syndrome-related Kaposi’s sarcoma (ll, 12).
`Activity has also been reported against nodular lymphomas,
`renal cell carcinoma, melanoma, and multiple myelome; how-
`ever, objective response rates remain less than 30% and dura-
`tions of response are generally short (13-16).
`While the IFNs have been studied for Over 30 years, the
`mechanism of their antitumor activity remains poorly under-
`stood. The 3 classes of IFN can be distinguished by their acid
`stability, their cell surface receptors, their primary sequence,
`and their chromosomal location and organization. IFNs have a
`number of biochemical actions, many of which can be attributed
`to gene activation and the stimulation of the synthesis of several
`proteins of known and unknown functions. One of the predom-
`inant cellular effects noted in vitro is the inhibition of cell cycle
`progression, with partial block in either the transition from Gu-
`G. to S, progression through S, or even generalized inhibition
`of cell cycle traverse (17). Because of the latter findings and the
`relatively weak cytotoxic effects of the IFNs, it has been pos-
`tulated that they may be best used in combination with other
`cytotoxic agents (18). This review will summarize and evaluate
`the clinical and preclinical studies that have used IFNs in
`combination with cytotoxic drugs.
`
`Received 1 If'i/‘i9; revised 2/2/90.
`The costs of publication of this article were defrayed in part by the payment
`of page charges. This article must therefore be hereby marked advertisement in
`accordance with 18 U.S.C. Section 1134 solely to indicate this fact.
`' Supported in part by American Cancer Society Research Grant Cit-479, by
`’ The abbreviations used are: IFN, interferon; BCNU, carrnustine [1.3-bis(2-
`Cancer Center Core Grant P30CAISJ3o-16 awarded by the National Cancer
`chloroethyleitrosoures}; s-FUra, s-fluorouracil; ADA. sdenosiue deamioase;
`Institute. and by a grant from the Mothers Foundation.
`DCF. Z’vdcoxyeoformycin; rIFN-o, recombinant human tar-interferon; DFMO,
`dilluoromethylornithine: VPlo. etoposide; MP. melphalan-prednisone; MU, "3'
`’ Recipient of a Career Development Award from the American Cancer Soci-
`ety. To whom requests for reprints should be addressed. at Department of
`units; ACNU. Hot-amino-I-methylpyrimidine-S-yl)mcthyl-J—{Z—chloroethyly}
`(cid:42)(cid:72)(cid:81)(cid:72)(cid:81)(cid:87)(cid:72)(cid:70)(cid:75)(cid:3)(cid:21)(cid:20)(cid:22)(cid:25)(cid:3)
`Oncology, Montefiore Medical Center, It] East llflth Street. Bronx, NY 10467.
`Genentech 2136
`(Z-chlaroethyIH-nitmsourea: MGBG. mitoguuone.
`(cid:38)(cid:72)(cid:79)(cid:79)(cid:87)(cid:85)(cid:76)(cid:82)(cid:81)(cid:3)(cid:89)(cid:17)(cid:3)(cid:42)(cid:72)(cid:81)(cid:72)(cid:81)(cid:87)(cid:72)(cid:70)(cid:75)(cid:3)
`3473
`Celltrion v. Genentech
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:26)(cid:16)(cid:19)(cid:20)(cid:20)(cid:21)(cid:21)
`Downloaded from cancerres.aacrjournals.org on April 9, 2018. © 1990 American Association for Cancer Resethc 2017—01122
`(cid:82)(cid:81)(cid:3)(cid:36)(cid:83)(cid:85)(cid:76)(cid:79)(cid:3)(cid:28)(cid:15)(cid:3)(cid:21)(cid:19)(cid:20)(cid:27)(cid:17)(cid:3)(cid:139)(cid:3)(cid:20)(cid:28)(cid:28)(cid:19)(cid:3)(cid:36)(cid:80)(cid:72)(cid:85)(cid:76)(cid:70)(cid:68)(cid:81)(cid:3)(cid:36)(cid:86)(cid:86)(cid:82)(cid:70)(cid:76)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3)(cid:73)(cid:82)(cid:85)(cid:3)(cid:38)(cid:68)(cid:81)(cid:70)(cid:72)(cid:85)(cid:3)(cid:53)(cid:72)(cid:86)(cid:72)(cid:68)(cid:85)(cid:70)(cid:75)(cid:17)(cid:3)
`(cid:70)(cid:68)(cid:81)(cid:70)(cid:72)(cid:85)(cid:85)(cid:72)(cid:86)(cid:17)(cid:68)(cid:68)(cid:70)(cid:85)(cid:77)(cid:82)(cid:88)(cid:85)(cid:81)(cid:68)(cid:79)(cid:86)(cid:17)(cid:82)(cid:85)(cid:74)
`(cid:39)(cid:82)(cid:90)(cid:81)(cid:79)(cid:82)(cid:68)(cid:71)(cid:72)(cid:71)(cid:3)(cid:73)(cid:85)(cid:82)(cid:80)(cid:3)
`
`

`

`INTERFERON—CYTDT‘DXIC AGENT COMBINATION CHEMOTHERAPY
`
`Table l Interactions offFN and chemothempeut‘ic agents.- in vitro cfonogent'c and proft'femtion assays, motor stem cell assays, and animal studies
`The extent of antineoplastic activity of combined lFN-anticancer drug treatments is indicated. The nature ofthe interaction as shown may not have been observed
`at all dose levels or schedules tested. “inactive“ means that neither component nor the combination had activity; “none” means that one component had no activity
`and had no effect when used in combination with an active agent; “additive" indicates that the antitumor effect of the combination was equal to that predicted from
`the use of individual active agents. Synergistic interactions were assessed by a variety of methods. including a combined effect greater than that predicted from the
`individual agents, and by isobologram analysis. Except when indicated as recombinant (Recomh.). [FN was purified or semipurilied. Human IFN-am was purified
`from normal human leukocytes. and human [FN—arh was purified from Namalwa lymphoblastoid cells. Human tumor stem cell assays (HT‘SCA) measured
`clonogenicity of primary human tumor cells in vitro: the number of responses and total number of tumors tested is indicated. in vivo assays measured tumor growth.
`animal survival or extent of metastases after tumor inoculation into syngeneic animals. or immunocompromised or nude mice. NSCLC. non-small cell lung carcinoma:
`
`ALL, acute lymphocytic leukemia.
`Tumor or cell line
`Interaction
`Ref.
`interferon
`Assay
`
`Cisplatin +
`Recomb. an,
`Human or...
`Recomb. an,
`Recomb. an
`Recomb. a).
`Murine a/fl
`Recomb. murine a
`Human up,
`Recomb. 8:.
`Human fl
`Recomb. "r
`Recomb. 1
`Recomb. 'r
`Recomb. ‘y
`Recomb. 1r
`Recomb. 1r
`Recomb. 1r
`Recomb. 1'
`
`Cyclophosphamide +
`Recomb. an
`Murine C-243 cell
`Murine L-celi
`Murine L-cell
`Murine tar/.6
`HLtI'fl-III in“.
`Human «3;,
`Human oA
`Human a“.
`Rat .6
`Donorubicin +
`Recomb. an.
`Recomb. an
`Human a A
`Human at A
`Recomb. om
`Recomb. an
`Recomb. an
`Recomb. an
`Recomb. on
`Human a;
`Human on,
`Human a”
`Murine a/fl
`Murine o/d
`Mouse been
`Recomb. 65..
`Human .3
`Human .8
`Human .3
`Human 3
`Recomb. 7
`Recomb. 1
`Recomb. ‘v
`Recomb. "r
`Recomb. 7
`Recomb. 'r
`Recomb. 1r
`Recomb. 'y
`Recomb. ‘y
`Recomb. 1r
`Recomb. 1
`Recon-1b. 'y
`S—Fluorouracil +
`Human on,
`Recomh. a).
`Recomb. a}.
`Recomb. on
`Recomb. o2.
`Recomb. a3.
`Recomb. a
`Recomb. a
`
`Cloning
`Cloning
`HTSCA
`HTSCA
`in vivo
`In viva
`in vivo
`in viva
`Proliferation
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`HTSCA
`
`HTSCA
`in vivo
`in vivo
`in viw
`in vivo
`in vivo'
`in vivo
`in viva
`in viva“
`in viva
`
`Proliferation
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`HTSCA
`HTSCA
`Proliferation
`in vivo‘
`Proliferation
`in vivo
`in viva
`HTSCA
`Cloning
`Proliferation
`Proliferation
`in viva“
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`HTSCA
`in vivo'
`
`Proliferation
`Proliferation
`Proliferation
`Proliferation
`Proliferation
`Proliferation
`Proliferation
`Proliferation
`
`BG-l human ovarian carcinoma
`RPM] 8226 human myeloma
`Human tumors
`Human tumors
`Human mesothelioma xenografts
`P388 murine leukemia
`MET—2 murine bladder carcinoma
`Human NSCLC aenografts
`ACHN human renal cell carcinoma
`HeLa human cervical
`KO-RCC-l human renal carcinoma
`RCC-nu-l human renal carcinoma
`BG-l human ovarian carcinoma
`SK-MEL-ZS human melanoma
`MEldfl human cervical carcinoma
`MCF—‘i‘ human breast carcinoma
`HEClA human endometrial carcinoma
`Human renal cell carcinoma
`
`Human ovarian tumors
`AKR murine lymphoma
`C1300 murine neuroblastoma
`LIZIO murine leukemia
`P388 murine leukemia
`Human breast carcinoma xenograft
`Human NSCLC xenograft
`TBD 932 hamster lymphcsarcoma
`HT117 human lymphoma
`LSITS rat Iiposarcoma
`
`CA46 human Burkitt's lymphoma
`BG-l human ovary carcinoma
`MCF-‘l' human breast carcinoma
`RPMI 8226 human myeloma
`136-! human ovarian carcinoma
`MCF—‘l human breast carcinoma
`CaSki human cervical carcinoma
`SK—MEL—23 human melanoma
`Multiple human tumors
`Multiple human tumors
`HOLT-4 human T-cell lymphoma
`Human breast xenograft
`MBT~2 murine bladder tumor
`MST-2 murine bladder tumor
`L121!) murine leukemia
`Multiple human tumors
`HeLa human cervical carcinoma
`I'LEpZ human laryngeal carcinoma
`Daudi human lymphoma
`Human glicblastomas
`BG-I human ovarian carcinoma
`SK-MEL-ZS human melanoma
`MEISO human cervical carcinoma
`CaSlti human cervical carcinoma
`HEC lA human endometria]
`MCF—T human breast carcinoma
`RPM] 8226 human myeloma
`KO-RCC-l human renal carcinoma
`RCC-nu-l human renal carcinoma
`RPM] 4188 human colon carcinoma
`Human renal cell carcinomas
`RPMI 4738 human colon carcinoma
`
`Synergistic
`Synergistic
`Synergistic (2/2)
`Additive (4/5)
`Synergistic
`Synergistic
`None
`Additive/synergistic
`Synergistic
`Synergisticfadditive
`Additive
`Synergistic
`Additive
`Additive
`Additive
`Additive
`Subadditive
`Additivefsynergistic {1/ l0)
`
`Synergistic
`Smnsistic
`Synergistic
`None
`Synergistic
`Synergistic
`Synergistic
`Synergistic
`None
`None
`
`Synergistic
`Synergistic
`Additive
`Additive
`Synergistic‘
`Synertistic
`Additive
`Subadditive
`Synergistic (9:13)
`Additivelsynergistic (3/10)
`Synergistic‘
`Synergistic
`Additive
`Inactive
`None
`None (0/2 5)
`Synergisticfadditive‘
`Synergistic
`Additive
`Additive
`Additive
`Additive
`Additive
`Additive
`Subadditive
`Additive
`Additive
`Synergistic
`Synergistic
`Synergistic
`Synergistic (8/1 1)
`Synergistic
`
`62
`61
`63
`62
`31
`25
`[30
`30
`131
`32. 70
`71'
`“t"?
`1'5
`1'5
`75
`75
`75
`'t"?
`
`63
`22
`24
`23
`132
`29
`
`28
`33
`21'
`
`I33
`63
`60
`60
`63, 64
`63. 64
`63. 64
`63, 64
`62
`63
`134
`29
`68
`63
`23
`1'6
`69. 70. 74
`74
`74
`34
`75
`75
`1‘5
`75
`75
`75
`75
`77
`77
`43
`T!
`43
`
`134
`MOLT—4 human ALL
`Synergistic
`135
`Additive
`Daudi human B—cell lymphoma
`135
`Additive
`MOLT-3 human T-oell lymphoma
`I35
`MOLT-‘t human T-oell lymphoma
`Synergistic
`I35
`K562 human leukemia
`Synergistic
`I35
`HT-29 human colon carcinoma
`Synergistic
`136. 13?
`None
`DIP-48 pancreatic carcinoma
`136. 13?
`Additive
`MKN—ZS and 74 human gastric carcinoma
`3474
`
`(cid:82)(cid:81)(cid:3)(cid:36)(cid:83)(cid:85)(cid:76)(cid:79)(cid:3)(cid:28)(cid:15)(cid:3)(cid:21)(cid:19)(cid:20)(cid:27)(cid:17)(cid:3)(cid:139)(cid:3)(cid:20)(cid:28)(cid:28)(cid:19)(cid:3)(cid:36)(cid:80)(cid:72)(cid:85)(cid:76)(cid:70)(cid:68)(cid:81)(cid:3)(cid:36)(cid:86)(cid:86)(cid:82)(cid:70)(cid:76)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3)(cid:73)(cid:82)(cid:85)(cid:3)(cid:38)(cid:68)(cid:81)(cid:70)(cid:72)(cid:85)(cid:3)(cid:53)(cid:72)(cid:86)(cid:72)(cid:68)(cid:85)(cid:70)(cid:75)(cid:17)(cid:3)
`(cid:70)(cid:68)(cid:81)(cid:70)(cid:72)(cid:85)(cid:85)(cid:72)(cid:86)(cid:17)(cid:68)(cid:68)(cid:70)(cid:85)(cid:77)(cid:82)(cid:88)(cid:85)(cid:81)(cid:68)(cid:79)(cid:86)(cid:17)(cid:82)(cid:85)(cid:74)
`(cid:39)(cid:82)(cid:90)(cid:81)(cid:79)(cid:82)(cid:68)(cid:71)(cid:72)(cid:71)(cid:3)(cid:73)(cid:85)(cid:82)(cid:80)(cid:3)
`Downloaded from cancerres.aacrjournals.org on April 9, 2018. © 1990 American Association for Cancer Research.
`
`

`

`lNTERFERON-CYTOTOXIC AGENT COMBINATION CHEMOTHERAPY
`
`
`
`
`Table l—Continued
` Interferon Assay Tumor or cell line Interaction Ref.
`
`
`
`Murine a/fl
`Proliferation
`Murine colon adenocarcinoma
`Synergistic
`46
`Recomb. 0:
`Proliferation
`HL-60 human leukemia
`Synergistic
`46
`Recomb. a
`Cloning
`HT—29 and SW48!) colon adenocarcinoma
`Synergistic
`104
`Recomb. an,
`HTSCA
`Multiple human tumors
`Synergistic (2)3)
`63
`Recomb. murine a
`In vivo
`MDT-2 mouse bladder carcinoma
`None
`130
`Recomb. a
`In vivo‘
`COLD 205 human colon adenocarcinoma
`Additive
`I38
`Recomh. .6
`Proliferation
`DF-48 pancreatic carcinoma
`Additive
`136. 131'
`Rocomh. ,6
`Proliferation
`MKN-ZS and 74 human gastric carcinoma
`Additive
`136. 13?
`Recomh. ,6
`Cloning
`PIT-19 and SSW-£30 colon adenocarcinoma
`Synergistic
`104
`Human .8
`Cloning
`HeLa human cervical carcinoma
`Additive/synergistic
`32, 70
`Human .6
`Cloning
`Wl-38 normal human fibroblasts
`None
`‘12. 139
`Human 5
`Cloning
`Wl-38-C'l' transformed fibroblasts
`Synergistic
`1'2. 139
`Human .6
`Proliferation
`KMM—I human myeloma
`Synergistic
`”II. 12. l39. 140
`Human .6
`Proliferation
`Raji human Burkitt‘s lymphoma
`Additive
`”II. 72‘ l39. 140
`Human .6
`Cloning
`MCF—"I human breast carcinoma
`None
`71. 1'2. l39. 140
`Recomh. .65...
`H'I'SCA
`Multiple human tumors
`None
`76
`Human ,8
`In viva“
`HeLa human cervical carcinoma
`Synergistic
`139
`Rat .6
`In vivo
`CC351 rat adenocarcinoma
`None
`141
`Reoornb. ‘y
`Cytolysis
`PIT—29 human colon carcinoma
`Synergistic
`'42
`Recomb. 1
`Proliferation
`RIF-43 pancreatic carcinoma
`Synergistic
`I36. I31'
`Recomb. y
`Proliferation
`MKN-28 and 1'4 human gastric carcinoma
`Subadditive
`136. 131'
`Reoornb. 7
`Proliferation
`Murine colon adenocarcinoma
`Synergistic
`46
`Recomb. 1r
`Cloning
`HT-29 and SW48!) colon carcinoma
`Synergistic
`I04
`Recomb. y
`Cloning
`KOmRCC-l human renal carcinoma
`Antagonistic
`77
`Recomb. 'v
`Cloning
`RCC-nu-l human renal carcinoma
`Additive
`71'
`Human recomh. 7
`Proliferation
`KM]: human colon carcinoma
`Additive
`39
`Murine recomb. 7
`Proliferation
`KM12 human colon carcinoma
`None
`39
`Human recomh. 1
`In vivo‘I
`KMIZ human colon carcinoma
`None
`39
`Murine recomb. 1r
`In viva“
`KMIZ human colon carcinoma
`Additive
`39
`
`Melphalan +
`Human an
`Human a A
`Recomh. an,
`Recomb. .6.
`Human i3
`
`Methotrexate +
`Recomb. an
`Recomb. or
`Mouse L—cell
`Recomh. .6 or 1!
`Recomh. a
`Recomb. ,6 or 1r
`
`Mitomycin C +
`Recomh. a).
`Murine n/fl
`Human ,6
`Human .6
`Human .6
`Recomb. 7
`Recomb. 1r
`
`Nitrogen mustard +
`Recomh. an.
`Reoomb. as.
`Recomh. as.
`Reoomh. an
`Recomb. cu.
`Vinblaatine +
`Human a A
`Human a A
`Human a A
`Recomb. a).
`Murine iii/.6
`Recomb. 8...
`Recomh. fl...
`Rocomh. y
`Recomb. 7
`Recomb. ‘y
`Rooomh. 1
`Recomh. ‘y
`Recomb. 1
`Recomh. y
`Recomh. y
`Vincristine +
`Human a“
`Human .8
`Human 3
`Human 6
`Human ,6
`
`Cloning
`In vivo
`HTSCA
`HTSCA
`Cloning
`
`Cloning
`Proliferation
`In vivo
`Proliferation
`Proliferation
`Proliferation
`
`In vivo‘
`Proliferation
`Proliferation
`Proliferation
`Cloning
`Cytolysis
`Cloning
`
`Proliferation
`Proliferation
`Proliferation
`Proliferation
`Proliferation
`
`Cloning
`Cloning
`Cloning
`Cloning
`In vivo
`Proliferation
`HTSCA
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`HTSCA
`
`Proliferation
`Cloning
`Proliferation
`Proliferation
`Proliferation
`
`RPM! 3226 human myeloma
`TED 932 hamster lymphoaarcoma
`Human lung tumors
`Multiple human tumors
`HeLa cervical carcinoma
`
`36-! human ovarian carcinoma
`DF—48 pancreatic carcinoma
`1.1210 murine leukemia
`DF—48 pancreatic carcinoma
`MKN-ZS and 1'4 gastric carcinoma
`MKN—28 and T4 gastric carcinoma
`
`Human mesothelioma xenograft
`MET—2 mouse bladder tumor
`H.EpZ human laryngeal carcinoma
`Daudi human lymphoma
`HeLa human cervical carcinoma
`HT—29 human colon carcinoma
`KO-RCC and ROC-nu-l human renal
`
`HT—29 human colon carcinoma
`Daudi human B-cell lymphoma
`HOLT-3 human Tall lymphoma
`HOLT-4 human T-cell lymphoma
`K562 human leukemia
`
`RPMI 8226 human myeloma
`MCF-‘I human breast carcinoma
`wiDr human colon carcinoma
`BG~1 human Ovarian carcinoma
`P333 murine leukemia
`ACHN human renal
`Multiple human tumors
`KO—ROC and RCC‘nu—I human renal
`30-] human ovarian carcinoma
`SK—MEL—ZS human melanoma
`CaSlti human cervical carcinoma
`MElfiD human cervical carcinoma
`MCF—‘I human breast carcinoma
`HECIA human endometrial carcinoma
`Human renal cell carcinomas
`
`HOLT-4 human ALL
`HeLa human cervical
`Daudi Burkitt's lymphoma
`M14 human melanoma
`H.Ep2 human laryngeal tumor
`3475
`
`Synergistic
`None
`Synergistic (1/2)
`None (0/26)
`Additive
`
`Synergistic
`None
`Additive
`Additive
`None
`Additive
`
`Synergistic
`Antagonistic
`Additive
`Additive
`Additive
`None
`Synergistic
`
`Synergistic
`Additive
`Additive
`Synergistic
`Synergistic
`
`Synergistic
`Synergistic
`Synergistic
`Synergistic
`Synergistic
`Synergistic
`None (0/26)
`Suhadditive
`Additive
`Suhadditive
`Suhadditive
`Suhadditive
`Additive
`Suhadditive
`Additive/synergistic (4/6:
`
`Additive
`Additive/synergistic
`Additive
`Additive
`synergistic
`
`64
`28
`63
`‘I6
`76
`
`64
`136, I37
`23
`136. L31
`136, l3?ll
`136‘ I37
`
`31
`63
`‘1'?
`77
`68
`142
`‘l‘i'
`
`I35
`I35
`135
`I35
`I35
`
`61
`61
`61
`64
`26
`26. 143
`1'6
`'i'i
`75
`75
`'i'S
`1'5
`'i'S
`TS
`77
`
`134
`70. ‘1‘"
`T4
`T4
`3'4
`
`(cid:82)(cid:81)(cid:3)(cid:36)(cid:83)(cid:85)(cid:76)(cid:79)(cid:3)(cid:28)(cid:15)(cid:3)(cid:21)(cid:19)(cid:20)(cid:27)(cid:17)(cid:3)(cid:139)(cid:3)(cid:20)(cid:28)(cid:28)(cid:19)(cid:3)(cid:36)(cid:80)(cid:72)(cid:85)(cid:76)(cid:70)(cid:68)(cid:81)(cid:3)(cid:36)(cid:86)(cid:86)(cid:82)(cid:70)(cid:76)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3)(cid:73)(cid:82)(cid:85)(cid:3)(cid:38)(cid:68)(cid:81)(cid:70)(cid:72)(cid:85)(cid:3)(cid:53)(cid:72)(cid:86)(cid:72)(cid:68)(cid:85)(cid:70)(cid:75)(cid:17)(cid:3)
`(cid:70)(cid:68)(cid:81)(cid:70)(cid:72)(cid:85)(cid:85)(cid:72)(cid:86)(cid:17)(cid:68)(cid:68)(cid:70)(cid:85)(cid:77)(cid:82)(cid:88)(cid:85)(cid:81)(cid:68)(cid:79)(cid:86)(cid:17)(cid:82)(cid:85)(cid:74)
`(cid:39)(cid:82)(cid:90)(cid:81)(cid:79)(cid:82)(cid:68)(cid:71)(cid:72)(cid:71)(cid:3)(cid:73)(cid:85)(cid:82)(cid:80)(cid:3)
`Downloaded from cancerres.aacrjournals.org on April 9, 2018. © 1990 American Association for Cancer Research.
`
`

`

`Table l-—~Continued
`
`Actinomycin D +
`Human pl
`Recomb. ‘y
`Recomb. 'y
`ACNU 4-
`Human t3
`Human ,d
`BCNU +
`Recomb. n
`C243 cell
`Bleomycin +
`Human at,
`Recomh. rug
`Marine “/5
`Human .6
`Murine am
`I —.fl—D—Arabinol'u r-
`anosylcytosine
`Human «L,
`Mouse L-cell
`Human 5,.
`Human ,cl
`DFMO +
`Human o3.
`Human m.
`Murine «(a
`Murine n/s
`Murine a or 1
`Recomb. a or .._,
`Recomb. a or 7
`Hydroxyurea +
`Human .6
`M636 +
`Rmmh. .8
`o-Mercaptopurine +
`Mouse L‘cell
`Human ,3
`Human ,3
`Neocarzinostatin +
`Human g
`Peplomycin +
`Human g
`Human fl
`Prednisone +
`Human a.”
`Thioguanine +
`Recomb. o3.
`Thiotepa +
`Murine all!
`‘ Assayed in nude mice.
`’ Similar results observed with 4’-deoxydoxorubicin. 4‘epidoxorubicin. and d'demethoxydosorubicin.
`‘ Similar results observed with aclacinomycin A.
`
`JDFI human renal carcinoma
`JDFI human renal carcinoma
`1.116 melanoma
`Blo melanoma
`Lewis lung carcinoma
`HM? human melanoma
`MDA-MB~23| breast carcinoma
`
`HeLa cervical carcinoma
`
`Multiple human tumors
`
`L1210 leukemia
`H.Ep2 laryngeal carcinoma
`Daudi lymphoma
`
`HeLa cervical carcinoma
`
`Wl-JS-Cl' transformed fibroblasts
`HeLa cervical carcinoma
`
`MOLT-nt human ALL
`
`Cloning
`In viva”
`Cloning
`In viva
`In viva
`Cloning
`Cloning
`
`Cloning
`
`HTSCA
`
`In vivo
`Proliferation
`Proliferation
`
`Cloning
`
`Cloning
`Cloning
`
`Proliferation
`
`Proliferation:
`
`Proliferation
`
`lNTERFERON-CYTOTOXIC AGENT COMBINATION CHEMOTHERAPY
`
` Interferon Assay Tumor or cell line
`
`
`
`Cloning
`Cloning
`Cloning
`
`Cloning
`In vivo‘
`
`In vivo
`In vt'vo
`
`Cloning
`Cloning
`Cloning
`Cloning
`In vivo
`
`HeLa cervical carcinoma
`RCC—nu—l renal cell carcinoma
`KO-RCC-l renal cell carcinoma
`
`HeLa cervical carcinoma
`GL-Z-JCK glioma
`
`A375 and Hlv‘l'lI melanoma
`LSTRA leukemia
`
`K562 human leukemia
`BG-l ovarian carcinoma
`1.1210 leukemia
`HeLa cervical carcinoma
`1.1210 leukemia
`
`Proliferation
`In vivo
`Proliferation
`Cloning
`
`HOLT-4 human ALL
`LIZID leukemia
`ACHN renal cell carcinoma
`HeLa cervical carcinoma
`
`Interaction
`
`None
`Synergistic
`Subadditive
`
`Synergistic
`Additive
`
`Synergistic
`Synergistic
`
`Synergistic
`Synergistic
`Synergistic
`Synergistic
`Synergistic
`
`Synergistic
`None
`Antagonistic
`None
`
`Synergistic
`Additive
`Synergistic
`Additive
`Additive
`Additive
`Additive
`
`None
`
`None
`
`None
`Suhadditive
`Suhadditive
`
`Synergistic
`
`Synergistic
`Synergistic
`
`Synergistic
`
`Ref.
`
`70
`77
`7T
`
`70
`34
`
`143
`2|
`
`58
`64
`58
`I39
`58
`
`134
`23
`131
`70
`
`I 11
`| [1
`128
`128
`128
`145
`145
`
`145
`
`‘16
`
`23
`77
`'I'I
`
`69
`
`139
`32
`
`134
`
`HL-oi‘.) leukemia
`Synergistic
`61'
`MET—2 bladder tumor 68 Antagonistic
`
`
`
`
`
`Studies in Animal Tumor Models in Combination with Antican-
`Cer Drugs
`
`not potentiate the activity of 6-mercaptopurine, doxorubicin,
`1-.8-o-arabinofuranosylcytosine. or cyclophosphamide against
`L1210 cells in viva, despite the fact that these agents alone had
`some activity (23). IFN did not potentiate the activity of cyclo-
`phosphamide against a spontaneous liposarcoma in rats {27)
`and at high doses actually abrogated the antitumor efficacy of
`cyclophosphamide in hamsters bearing TBD 932 lymphosar—
`coma cells (28).
`The studies cited above demonstrated the value of IFN in
`
`Studies evaluating the antitumor activity of IFN in combi-
`nation with cytotoxic agents were begun shortly after it was
`recOgnized that IFN possessed antitumor activity in experimen-
`tal animal tumor systems (19, 20). The earliest studies against
`murine leukemias were largely empirical in design and were
`based on the assumption that cytotoxic agents were most useful
`for debulking large tumor volume and that the resultant micro-
`scopic residual disease would best be eradicated with IFN
`“immunotherapy” (9). The efficacy ofthis approach was judged
`by comparing survival of animals treated with the combination
`of a single dose of cytotoxic agent and multiple doses of IFN
`with that of animals treated with either agent alone (Table 1).
`Initial studies reported activity of murine IFN when it was
`administered in combination with BCNU. cyclophosphamide,
`or methotrexate to mice bearing spontaneous or implanted
`leukemia and lymphomas (21—23). Murine IFN also increased
`survival in mice with neuroblastoma cells after administration
`
`enhancing the activity of chemotherapeutic agents In vivo
`against rodent tumors. although those studies which used rela-
`tively crude preparations of IFN must be interpreted with
`caution. More recently these observations have been extended
`to human tumor xenografts and human tumor cells implanted
`in nude mice (Table 1). Many of these studies also used highly
`purified natural or recombinant IFN. Human IFN-o was found
`to increase the antitumor activity of cyclophosphamide, doxo—
`rubicin1 cisplatin, and mitomycin C (29—31). Activity was ob-
`served in human breast tumor (29). non-small cell lung cancer
`(30). and human mesothelioma xenografts (31). Human fibro—
`blast lFN—fi enhanced the growth inhibition of 5-fluorouracil
`of cyclophOSpltarnide (24) and in mice with P388 leukemia cells
`after treatment with cisplatin (25) or vinblastine {26). Not all
`against implanted human cervical carcinoma (HeLa) cells (32).
`studies yielded positive results. however. For example, IFN did
`Other studies failed to show any significant potentiation by
`3476
`
`(cid:82)(cid:81)(cid:3)(cid:36)(cid:83)(cid:85)(cid:76)(cid:79)(cid:3)(cid:28)(cid:15)(cid:3)(cid:21)(cid:19)(cid:20)(cid:27)(cid:17)(cid:3)(cid:139)(cid:3)(cid:20)(cid:28)(cid:28)(cid:19)(cid:3)(cid:36)(cid:80)(cid:72)(cid:85)(cid:76)(cid:70)(cid:68)(cid:81)(cid:3)(cid:36)(cid:86)(cid:86)(cid:82)(cid:70)(cid:76)(cid:68)(cid:87)(cid:76)(cid:82)(cid:81)(cid:3)(cid:73)(cid:82)(cid:85)(cid:3)(cid:38)(cid:68)(cid:81)(cid:70)(cid:72)(cid:85)(cid:3)(cid:53)(cid:72)(cid:86)(cid:72)(cid:68)(cid:85)(cid:70)(cid:75)(cid:17)(cid:3)
`(cid:70)(cid:68)(cid:81)(cid:70)(cid:72)(cid:85)(cid:85)(cid:72)(cid:86)(cid:17)(cid:68)(cid:68)(cid:70)(cid:85)(cid:77)(cid:82)(cid:88)(cid:85)(cid:81)(cid:68)(cid:79)(cid:86)(cid:17)(cid:82)(cid:85)(cid:74)
`(cid:39)(cid:82)(cid:90)(cid:81)(cid:79)(cid:82)(cid:68)(cid:71)(cid:72)(cid:71)(cid:3)(cid:73)(cid:85)(cid:82)(cid:80)(cid:3)
`Downloaded from cancerres.aacrjournalsorg on April 9, 2018. © 1990 American Association for Cancer Research.
`
`

`

`lNTERFERON-CYTOTOXIC AGENT COMBINATION CHEMOTHERAPY
`
`the human
`activity of the chemotherapeutic agents against
`xenografts (41). Conversely, murine IFN did not potentiate the
`antitumor activity of the same drugs against the xenografts,
`despite the fact that it presumably produced multiple host-
`dependent effects (42). It is likely that both direct antitumor
`effects and host-mediated actions occur in viva, but the relative
`contribution of each may vary depending upon the species of
`IFN used.
`
`Undoubtedly interactions of IFN and anticancer agents in
`viva are complex and multifaceted. For example, daily injec«
`tions of IFN-7 did not affect the s.c. growth of human colon
`carcinoma cells in nit/nu mice but did synergistically enhance
`the antitumor activity of doxorubicin when the two were used
`simultaneously (43). However, when the cells were inoculated
`i.v., IFN-7 had both activity alone and also enhanced the
`activity of doxorubicin against the formation of pulmonary
`metastases in this tumor model. Other studies suggest that IFN
`may be particularly active against experimental metastases after
`i.v. inoculation of mice with melanoma or erythroleukemia cells
`(44, 45). In the latter study, although both the IFN and several
`cytotoxic agents were active against tumor inoculated i.p., only
`the IFN was active against the i.v.-inoculated tumor, suggesting
`that the efficacy of IFN-drug combinations may reflect actions
`on different populations of tumor cells or on tumor cells at
`different anatomical sites. or interest
`in this regard is the
`observation that IFN had a selective growth-suppressive effect
`on the hyperdiploid compartment of a murine colon adenocar-
`cinoma cell line (46). Further investigations into the effect of
`IFN on aneuploid cells and micrometastases in combination
`with anticancer drugs would be very useful.
`
`Host Protective Effects
`
`An alternative indirect mechanism for the interaction of IFN
`
`and anticancer drugs was reported by Stolfi at at. (47). Partially
`purified or recombinant IFN-a: was found to protect mice from
`the toxic effects of S-fluorouracil {47, 48). This protection was
`manifested as decreases in body weight loss, leukopenia, and
`mortality. The schedule of administration of the two agents, 5-
`FUra followed by multiple injections of IFN, is similar to that
`used in many of the in viva studies described above. These
`investigators suggest that the mechanism for the protective
`effect of the IFN was the suppression of proliferation of the
`normal bone marrow cells of the host, thus rendering them less
`sensitive to the cytotoxic actions of the S—FUra. Presumably
`the protective effect of‘ IFN would allow higher doses of cyto-
`toxic drugs to be used, thus increasing their antitumor activity
`(48).
`
`Effects on Drug-metabolizing Enzymes
`
`IFN-tr of the activity of cyclophosphamide against a variety of
`human xenografts (testicular, colonic, squamous cell, and renal
`cell carcinomas; melanoma; and non-Hodgkin‘s lymphoma)
`(33), although in the latter trials IFN was administered 24 h
`after the alkylating agent, suggesting that Schedule and se-
`quence may be of critical importance. Interestingly, IFN also
`enhanced the activity of radiation against human glioma xeno-
`grafts and monolayer cultures (34, 35).
`These studies indicated that IFN potentiates the activity of a
`number of clinically useful drugs against a variety of human
`tumors in many but not all possible combinations and tumor
`models. In most of the cases where potentiation was observed,
`IFN alone had only weak antitumor activity; however, IFN
`seemed to be most effective in combination with drugs that
`alone possessed substantial activity against the specific tumor
`(31). The experiments described above cannot resolve the ques~
`tion of the mechanism of interaction between IFN and the
`
`cytotoxic agents. It seems likely that the interactions observed
`were not solely the consequence of the combined effect of two
`cytoreductive agents, since the enhanced activity of the drug-
`IFN combination was observed even in instances where IFN
`
`alone lacked activity, and IFN also failed to potentiate the
`activity of other efficacious drugs. At least two broadly defined
`alternative modes of interaction can be envisioned: IFN might
`biochemically modulate the activity of anticancer drugs by, e.g.,
`affecting critical target enzymes, repair mechanisms, or detOx-
`ification pathways within the tumor cell; alternatively IFN
`could have actions on the host animal that could affect
`the
`
`activity of the anticancer agent, either directly or indirectly.
`These may include actions on drug-metabolizing enzymes that
`activate or inactivate the drugs, protective effects on normal
`host tisSues which enhance the usefulness of the cytotoxic agent,
`and effects on the immune system which produce synergistic
`antitumor actions when used in combination with other chem-
`
`otherapeutic drugs.
`
`Indirect Antitumor Effects in Viva
`
`The earliest evidence for an indirect antitumor effect of IFN
`was combined in vitra-in viva studies with mouse LIZIO cells.
`IFN directly inhibited the proliferation of L1210 cells in vitra,
`and a variant cell line that was resistant to this effect was
`
`isolated. When tested in viva, IFN had activity against both the
`sensitive and resis