[CANCER RESEARCH50, 3473-3486, June 15, 1990]
`
`Review
`
`Antineoplastic Activity of the Combination of Interferon and Cytotoxic Agents
`against Experimental and Human Malignancies: A Review'
`
`Scott Wadler? and Edward L. Schwartz
`Department ofOncology, Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10467
`
`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 cytokinetic
`effects for IFN, a more interesting role derives from its ability to
`synergistically 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 vivo interactions between IFN and cyto-
`toxic agents involve an additional layer of complexity because of the
`potential effects of the biological 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 incorporate information on dose, scheduling, and se-
`quence of drug administration into clinical trials. Preliminary clinical
`studies with IFN-a and the fluorinated pyrimidine, 5-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 chemotherapyhas 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 tumorcells, with someselectivity
`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 combinationsutilize agents with different
`mechanisms of action (3); and drug combinations should be
`selected to minimize any overlappingtoxicities 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 assumptionsfor 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 compoundsinto clinical
`regimensinclude: (a) their poorly understood mechanism of
`action (5); (4) their relatively weak or absent cytotoxic activities
`(6); (c) a novel spectrum oftoxicities (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 IFNs? are a family of naturally occurring glycoproteins
`which shareantiviral, immunomodulatory, and antiproliferative
`effects. Discovered in 1957 by Isaacs and Lindenmann (10),
`their antitumoractivity has been the most thoroughly studied
`of the biological response modifiers. Early clinical trials estab-
`lished activity for IFNs as single agents against tworelatively
`uncommon malignancies, hairy cell leukemia and acquired im-
`munodeficiency syndrome-related Kaposi’s sarcoma(11, 12).
`Activity has also been reported against nodular lymphomas,
`renal cell carcinoma, melanoma, and multiple myeloma; 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
`numberof biochemical actions, many of which can be attributed
`to gene activation and the stimulation of the synthesis of several
`proteins of known and unknownfunctions. Oneof the predom-
`inant cellular effects noted in vitro is the inhibitionofcell cycle
`progression, with partial block in either the transition from Go-
`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 11/7/79; 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 1734 solely to indicate this fact.
`3 The abbreviations used are: IFN, interferon; BCNU, carmustine[1,3-bis(2-
`‘ Supported in part by American Cancer Society Research Grant CH-479, by
`chloroethyl)-1-nitrosourea]; 5-FUra, 5-fluorouracil; ADA, adenosine deaminase;
`Cancer Center Core Grant P30CA13330-16 awarded by the National Cancer
`Institute, and by a grant from the Mathers Foundation.
`DCF, 2'-deoxycoformycin; rIFN-a, recombinant human a-interferon; DFMO,
`difluoromethylornithine; VP16, etoposide; MP, melphalan-prednisone; MU, 10°
`? 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, 1-(4-amino-2-methylpyrimidine-5-y1)methyl-3-(2-chloroethyl)-3-
`(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, 111 East 210th Street, Bronx, NY 10467,—_(2-chloroethyl)-3-nitrosourea; MGBG, mitoguazone. Genentech 2136
`(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)
`Downloadedfrom cancerres.aacrjournals.org on April 9, 2018. © 1990 American Association for Cancer Reseliré ew 122
`(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-CYTOTOXIC AGENT COMBINATION CHEMOTHERAPY
`
`Table 1 Interactions ofIFN and chemotherapeutic agents: in vitro clonogenic and proliferation assays, tumor stem cell assays, and animal studies
`The extent of antineoplastic activity of combined IFN-anticancer drug treatmentsis indicated. The nature of the 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 componenthad noactivity
`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 (Recomb.), IFN was purified or semipurified. Human IFN-a,,, was purified
`from normal human leukocytes, and human IFN-a,, was purified from Namalwa lymphoblastoid cells. Human tumor stem cell assays (HTSCA) measured
`clonogenicity of primary human tumorcells in vitro; the number of responses and total number of tumors tested is indicated. Jn vivo assays measured tumor growth,
`animal survival or extent of metastases after tumor inoculation into syngeneic animals, or immunocompromised or nude mice. NSCLC, non-smallcell lung carcinoma;
`
`ALL, acute lymphocytic leukemia.
`Tumor or cell line
`Interaction
`Ref.
`Interferon
`Assay
`
`Cisplatin +
`Recomb.ax
`Human apy
`Recomb. a»
`Recomb. a»
`Recomb.a2,
`Murine a/3
`Recomb. murine a
`Human a,
`Recomb. fsa
`Human 8
`Recomb. +
`Recomb.+
`Recomb.+
`Recomb. +
`Recomb.+
`Recomb.+
`Recomb. +
`Recomb. +
`
`Cyclophosphamide +
`Recomb.a»
`Murine C-243cell
`Murine L-cell
`Murine L-cell
`Murine a/8
`Human ay
`Human a,
`Human aA
`Human ap
`Rat 8
`Doxorubicin +
`Recomb. ax,
`Recomb. a2,
`Human a A
`Human a A
`Recomb. a2
`Recomb.az,
`Recomb. a2,
`Recomb. a2»
`Recomb.oz,
`Human ae,
`Humana,
`Humana,
`Murine a/f
`Murine a/f
`Mouse L-cell
`Recomb. fse
`Human @
`Human 8
`Human ¢
`Human 8
`Recomb.+
`Recomb. +
`Recomb.+
`Recomb. +
`Recomb. +
`Recomb.+
`Recomb. +
`Recomb. +
`Recomb. +
`Recomb. +
`Recomb. +
`Recomb.+
`§-Fluorouracil +
`Human a,
`Recomb. a2,
`Recomb.a2,
`Recomb.am
`Recomb.a,
`Recomb. Op,
`Recomb.a
`Recomb.a
`
`Cloning
`Cloning
`HTSCA
`HTSCA
`In vivo
`In vivo
`In vivo
`In vivo
`Proliferation
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`HTSCA
`
`HTSCA
`In vivo
`In vivo
`In vivo
`In vivo
`In vivo*
`In vivo
`In vivo
`In vivo®
`In vivo
`
`Proliferation
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`HTSCA
`HTSCA
`Proliferation
`In vivo*
`Proliferation
`In vivo
`In vivo
`HTSCA
`Cloning
`Proliferation
`Proliferation
`In vivo*
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`Cloning
`HTSCA
`In vivo"
`
`Proliferation
`Proliferation
`Proliferation
`Proliferation
`Proliferation
`Proliferation
`Proliferation
`Proliferation
`
`62
`61
`63
`62
`31
`25
`130
`30
`131
`32, 70
`77
`77
`15
`75
`75
`75
`75
`77
`
`132
`
`BG-1 humanovarian carcinoma
`RPMI 8226 human myeloma
`Human tumors
`Human tumors
`Human mesothelioma xenografts
`P388 murine leukemia
`MBT-2 murine bladder carcinoma
`Human NSCLCxenografts
`ACHN human renalcell carcinoma
`HeLa humancervical
`KO-RCC-1 human renal carcinoma
`RCC-nu-1 human renal carcinoma
`BG-1 human ovarian carcinoma
`SK-MEL-28 human melanoma
`ME180 humancervical carcinoma
`MCF-7 human breast carcinoma
`HECIA humanendometrial carcinoma
`Humanrenal cell carcinoma
`
`Humanovarian tumors
`AKRmurine lymphoma
`C1300 murine neuroblastoma
`L1210 murine leukemia
`P388 murine leukemia
`Human breast carcinoma xenograft
`Human NSCLC xenograft
`TBD 932 hamster lymphosarcoma
`HT117 human lymphoma
`LS175 rat liposarcoma
`
`CA46 human Burkitt's lymphoma
`BG-1 human ovary carcinoma
`MCF-7 humanbreast carcinoma
`RPMI 8226 human myeloma
`BG-1 human ovarian carcinoma
`MCF-7 human breast carcinoma
`CaSki human cervical carcinoma
`SK-MEL-28 human melanoma
`Multiple human tumors
`Multiple human tumors
`MOLT-4 human T-cell lymphoma
`Humanbreast xenograft
`MBT-2 murine bladder tumor
`MBT-2 murine bladder tumor
`L1210 murine leukemia
`Multiple human tumors
`HeLa human cervical carcinoma
`H.Ep2 human laryngeal carcinoma
`Daudi human lymphoma
`Human glioblastomas
`BG-1 human ovarian carcinoma
`SK-MEL-28 human melanoma
`ME180 human cervical carcinoma
`CaSki humancervical carcinoma
`HEC 1A human endometrial
`MCF-7 human breast carcinoma
`RPMI 8226 human myeloma
`KO-RCC-1 human renal carcinoma
`RCC-nu-1 human renal carcinoma
`RPMI 4788 human colon carcinoma
`Human renalcell carcinomas
`RPMI 4788 human colon carcinoma
`
`Synergistic
`Synergistic
`Synergistic (2/2)
`Additive (4/5)
`Synergistic
`Synergistic
`None
`Additive/synergistic
`Synergistic
`Synergistic/additive
`Additive
`Synergistic
`Additive
`Additive
`Additive
`Additive
`Subadditive
`Additive/synergistic (7/10)
`
`Synergistic
`Synergistic
`Synergistic
`None
`Synergistic
`Synergistic
`Synergistic
`Synergistic
`None
`None
`
`Synergistic
`Synergistic
`Additive
`Additive
`Synergistic?
`Synertistic
`Additive
`Subadditive
`Synergistic (9/13)
`Additive/synergistic (3/10)
`Synergistic*
`Synergistic
`Additive
`Inactive
`None
`None (0/25)
`Synergistic/additive®
`Synergistic
`Additive
`Additive
`Additive
`Additive
`Additive
`Additive
`Subadditive
`Additive
`Additive
`Synergistic
`Synergistic
`Synergistic
`Synergistic (8/11)
`Synergistic
`
`134
`MOLT-4 human ALL
`Synergistic
`135
`Additive
`Daudi human B-cell lymphoma
`135
`Additive
`MOLT-3 human T-cell lymphoma
`135
`MOLT-4 human T-cell lymphoma
`Synergistic
`135
`K562 human leukemia
`Synergistic
`135
`HT-29 human colon carcinoma
`Synergistic
`136, 137
`None
`DF-48 pancreatic carcinoma
`136, 137
`Additive
`MKN-28 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)
`Downloadedfrom cancerres.aacrjournals.org on April 9, 2018. © 1990 American Association for Cancer Research.
`
`

`

`INTERFERON-CYTOTOXIC AGENT COMBINATION CHEMOTHERAPY
`
`Table 1—Continued
`
`Interferon
`Assay
`Tumor or cell line
`Interaction
`Ref.
`Murine a/8
`Proliferation
`Murine colon adenocarcinoma
`Synergistic
`Recomb.a
`Proliferation
`HL-60 human leukemia
`Synergistic
`Recomb. a
`Cloning
`HT-29 and SW-480 colon adenocarcinoma
`Synergistic
`Recomb.ax
`HTSCA
`Multiple human tumors
`Synergistic (2/5)
`Recomb. murine a
`In vivo
`MBT-2 mouse bladder carcinoma
`None
`Recomb.a
`In vivo*
`COLO 205 human colon adenocarcinoma
`Additive
`Recomb. 8
`Proliferation
`DF-48 pancreatic carcinoma
`Additive
`Recomb.8
`Proliferation
`MKN-28 and 74 humangastric carcinoma
`Additive
`Recomb. 8
`Cloning
`HT-29 and SW-480 colon adenocarcinoma
`Synergistic
`Human 8
`Cloning
`HeLa human cervical carcinoma
`Additive/synergistic
`Human 6
`Cloning
`WI-38 normal humanfibroblasts
`None
`Human 8
`Cloning
`WI-38-CT transformed fibroblasts
`Synergistic
`Human @
`Proliferation
`KMM.-1 human myeloma
`Synergistic
`Human 8
`Proliferation
`Raji human Burkitt’s lymphoma
`Additive
`Human §
`Cloning
`MCF-7 humanbreast carcinoma
`None
`Recomb. Bs.
`HTSCA
`Multiple human tumors
`None
`Human 8
`In vivo*
`HeLa humancervical carcinoma
`Synergistic
`Rat 8
`In vivo
`CC351 rat adenocarcinoma
`None
`Recomb.+
`Cytolysis
`HT-29 humancolon carcinoma
`Synergistic
`Recomb.+
`Proliferation
`DF-48 pancreatic carcinoma
`Synergistic
`Recomb.+
`Proliferation
`MKN-28 and 74 humangastric carcinoma
`Subadditive
`Recomb.+
`Proliferation
`Murine colon adenocarcinoma
`Synergistic
`Recomb.+
`Cloning
`HT-29 and SW-480 colon carcinoma
`Synergistic
`Recomb. +
`Cloning
`KO-RCC-1 human renal carcinoma
`Antagonistic
`Recomb.+
`Cloning
`RCC-nu-1 human renal carcinoma
`Additive
`Human recomb. +
`Proliferation
`KM12 humancolon carcinoma
`Additive
`Murine recomb.+
`Proliferation
`KM12 humancolon carcinoma
`None
`Human recomb.+
`In vivo"
`KM12 humancolon carcinoma
`None
`Murine recomb. >
`In vivo*
`KM12 humancolon carcinoma
`Additive
`
`46
`46
`104
`63
`130
`138
`136, 137
`136, 137
`104
`32,70
`72, 139
`72, 139
`71, 72, 139, 140
`71, 72, 139, 140
`71, 72, 139, 140
`76
`139
`141
`142
`136, 137
`136, 137
`46
`104
`77
`77
`39
`39
`39
`39
`
`Melphalan +
`Human a
`Human a A
`Recomb. a»
`Recomb.fur
`Human ¢
`
`Methotrexate +
`Recomb.a2,
`Recomb. a
`Mouse L-cell
`Recomb. 8 or +
`Recomb. a
`Recomb. 8 or
`
`Mitomycin C +
`Recomb. a2,
`Murine a/8
`Human 8
`Human §
`Human 8
`Recomb.+
`Recomb.+
`
`Nitrogen mustard +
`Recomb.a2,
`Recomb. a2,
`Recomb. a2.
`Recomb. a2,
`Recomb.az.
`Vinblastine +
`Human a A
`Human @ A
`Human a A
`Recomb.ox
`Murine «/8
`Recomb. 8...
`Recomb. Bur
`Recomb. +
`Recomb. +
`Recomb. +
`Recomb. +
`Recomb.+
`Recomb.+
`Recomb. +
`Recomb. +
`Vincristine +
`Human a,
`Human 8
`Human 8
`Human §
`Human 8
`
`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
`
`RPMI 8226 human myeloma
`TBD 932 hamster lymphosarcoma
`Human lung tumors
`Multiple human tumors
`HeLa cervical carcinoma
`
`BG-1 humanovarian carcinoma
`DF-48 pancreatic carcinoma
`L1210 murine leukemia
`DF-48 pancreatic carcinoma
`MKN-28 and 74 gastric carcinoma
`MKN-28 and 74gastric carcinoma
`
`Human mesothelioma xenograft
`MBT-2 mouse bladder tumor
`H.Ep2 humanlaryngeal carcinoma
`Daudi human lymphoma
`HeLa humancervical carcinoma
`HT-29 humancolon carcinoma
`KO-RCC and RCC-nu-1 humanrenal
`
`HT-29 humancolon carcinoma
`Daudi human B-cell lymphoma
`MOLT-3 human T-cell lymphoma
`MOLT-4 human T-cell lymphoma
`KS62 human leukemia
`
`RPMI 8226 human myeloma
`MCEF-7 humanbreast carcinoma
`WiDr humancolon carcinoma
`BG-1 human ovarian carcinoma
`P388 murine leukemia
`ACHN humanrenal
`Multiple human tumors
`KO-RCC and RCC-nu-1 humanrenal
`BG-1 humanovarian carcinoma
`SK-MEL-28 human melanoma
`CaSki human cervical carcinoma
`ME180 humancervical carcinoma
`MCF-7 humanbreast carcinoma
`HECIA human endometrial carcinoma
`Humanrenalcell carcinomas
`
`MOLT-4 human ALL
`HeLa humancervical
`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)
`Subadditive
`Additive
`Subadditive
`Subadditive
`Subadditive
`Additive
`Subadditive
`Additive/synergistic (4/6.
`
`Additive
`Additive/synergistic
`Additive
`Additive
`Synergistic
`
`64
`28
`63
`16
`70
`
`64
`136, 137
`23
`136, 137
`136, 137
`136, 137
`
`31
`68
`77
`77
`68
`142
`77
`
`135
`135
`135
`135
`135
`
`61
`61
`61
`64
`26
`26, 143
`76
`77
`75
`75
`75
`75
`75
`75
`TW
`
`134
`70, 74
`74
`74
`74
`
`(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)
`Downloadedfrom cancerres.aacrjournals.org on April 9, 2018. © 1990 American Association for Cancer Research.
`
`

`

`Table 1—Continued
`
`Actinomycin D +
`Human ¢@
`Recomb. +
`Recomb.
`ACNU +
`Human 8
`Human p
`BCNU +
`Recomb. «
`C243 cell
`Bleomycin +
`Human a,
`Recomb.ay,
`Murine a/f
`Human
`Murine a/p
`1-8-p-Arabinofur-
`anosylcytosine
`Human a,
`Mouse L-cell
`Human fs
`Human ¢
`DFMO +
`Human ay,
`Humana,
`Murine «/8
`Murine a/@
`Murine « or y
`Recomb.a or y
`Recomb. a or y
`Hydroxyurea +
`Human &
`MGBG +
`Recomb. 8
`6-Mercaptopurine +
`Mouse L-cell
`Human 8
`Human 8
`Neocarzinostatin +
`Human 8
`Peplomycin +
`Human 8
`Human 8
`Prednisone +
`Humana1,
`Thioguanine +
`Recomb.a»,
`Thiotepa +
`Murine a/8
`* Assayed in nude mice.
`° Similar results observed with 4’-deoxydoxorubicin, 4’-epidoxorubicin, and 4’-demethoxydoxorubicin.
`© Similar results observed with aclacinomycin A.
`
`JDFI human renal carcinoma
`JDF1 human renal carcinoma
`B16 melanoma
`B16 melanoma
`Lewis lung carcinoma
`HM7 human melanoma
`MDA-MB-231 breast carcinoma
`
`HeLa cervical carcinoma
`
`Multiple human tumors
`
`L1210 leukemia
`H.Ep2laryngeal carcinoma
`Daudi lymphoma
`
`HeLacervical carcinoma
`
`WI-38-CT transformed fibroblasts
`HeLa cervical carcinoma
`
`MOLT-4 human ALL
`
`Cloning
`In vivo?
`Cloning
`In vivo
`In vivo
`Cloning
`Cloning
`
`Cloning
`
`HTSCA
`
`In vivo
`Proliferation
`Proliferation
`
`Cloning
`
`Cloning
`Cloning
`
`Proliferation
`
`Proliferation
`
`Proliferation
`
`INTERFERON-CYTOTOXIC AGENT COMBINATION CHEMOTHERAPY
`
` Interferon Assay Tumororcell line
`
`
`
`Cloning
`Cloning
`Cloning
`
`Cloning
`In vivo*
`
`In vivo
`In vivo
`
`Cloning
`Cloning
`Cloning
`Cloning
`In vivo
`
`HeLa cervical carcinoma
`RCC-nu-1 renalcell carcinoma
`KO-RCC-1 renal cell carcinoma
`
`HeLa cervical carcinoma
`GL-2-JCK glioma
`
`A375 and HM7 melanoma
`LSTRA leukemia
`
`K562 humanleukemia
`BG-1 ovarian carcinoma
`L1210 leukemia
`HeLa cervical carcinoma
`L1210 leukemia
`
`Proliferation
`In vivo
`Proliferation
`Cloning
`
`MOLT-4 human ALL
`L1210 leukemia
`ACHN renalcell 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
`Subadditive
`Subadditive
`
`Synergistic
`
`Synergistic
`Synergistic
`
`Synergistic
`
`Ref.
`
`70
`77
`77
`
`70
`34
`
`143
`21
`
`58
`64
`58
`139
`58
`
`134
`23
`131
`70
`
`lil
`lll
`128
`128
`128
`145
`145
`
`145
`
`76
`
`23
`17
`77
`
`69
`
`139
`32
`
`134
`
`HL-60 leukemia
`Synergistic
`67
`MBT-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-p-arabinofuranosylcytosine, or cyclophosphamide against
`L1210 cells in vivo, despite the fact that these agents alone had
`someactivity (23). IFN did not potentiate the activity of cyclo-
`Studies evaluating the antitumor activity of IFN in combi-
`phosphamide against a spontaneous liposarcoma in rats (27)
`nation with cytotoxic agents were begun shortly after it was
`and at high doses actually abrogated the antitumorefficacy of
`recognized that IFN possessed antitumoractivity in experimen-
`cyclophosphamide in hamsters bearing TBD 932 lymphosar-
`tal animal tumor systems (19, 20). The earliest studies against
`comacells (28).
`murine leukemias were largely empirical in design and were
`The studies cited above demonstrated the value of IFN in
`based on the assumption that cytotoxic agents were most useful
`enhancing the activity of chemotherapeutic agents in vivo
`for debulking large tumor volumeandthatthe resultant micro-
`against rodent tumors, although those studies which used rela-
`scopic residual disease would best be eradicated with IFN
`tively crude preparations of IFN must be interpreted with
`“immunotherapy” (9). The efficacy of this approach was judged
`by comparing survival of animals treated with the combination
`caution. More recently these observations have been extended
`of a single dose of cytotoxic agent and multiple doses of IFN
`to human tumor xenografts and human tumorcells implanted
`in nude mice (Table 1). Many ofthese studies also used highly
`with that of animals treated with either agent alone (Table 1).
`purified natural or recombinant IFN. Human IFN-a was found
`Initial studies reported activity of murine IFN when it was
`to increase the antitumoractivity of cyclophosphamide, doxo-
`administered in combination with BCNU, cyclophosphamide,
`rubicin, cisplatin, and mitomycin C (29-31). Activity was ob-
`or methotrexate to mice bearing spontaneous or implanted
`served in human breast tumor (29), non-small cell lung cancer
`leukemia and lymphomas (21-23). Murine IFN also increased
`survival in mice with neuroblastomacells after administration
`(30), and human mesothelioma xenografts (31). Human fibro-
`blast IFN-@ enhanced the growth inhibition of 5-fluorouracil
`of cyclophosphamide (24) and in mice with P388 leukemiacells
`against implanted humancervical carcinoma (HeLa)cells (32).
`after treatment with cisplatin (25) or vinblastine (26). Notall
`Other studies failed to show any significant potentiation by
`studies yielded positive results, however. For example, IFN did
`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)
`Downloadedfrom cancerres.aacrjournals.org on April 9, 2018. © 1990 American Association for Cancer Research.
`
`

`

`INTERFERON-CYTOTOXIC AGENT COMBINATION CHEMOTHERAPY
`
`IFN-a of the activity of cyclophosphamideagainst a variety of
`human xenografts (testicular, colonic, squamouscell, 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 ofcritical importance. Interestingly, IFN also
`enhanced theactivity of radiation against human glioma xeno-
`grafts and monolayercultures (34, 35).
`Thesestudies indicated that IFN potentiates the activity of a
`numberofclinically useful drugs against a variety of human
`tumors in many but notall 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 notsolely the consequence of the combinedeffect 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 modesof interaction can be envisioned: IFN might
`biochemically modulate the activity of anticancer drugsby,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 mayinclude 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 Vivo
`
`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-
`dependenteffects (42). It is likely that both direct antitumor
`effects and host-mediated actions occur in vivo, but the relative
`contribution of each may vary depending upon the species of
`IFN used.
`Undoubtedly interactions of IFN and anticancer agents in
`vivo are complex and multifaceted. For example, daily injec-
`tions of IFN-y did not affect the s.c. growth of human colon
`carcinomacells in nu/nu mice but did synergistically enhance
`the antitumoractivity of doxorubicin when the two were used
`simultaneously (43). However, when the cells were inoculated
`i.v., IFN-y 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
`maybe particularly active against experimental metastasesafter
`i.v. inoculation of mice with melanomaor erythroleukemiacells
`(44, 45). In the latter study, although both the IFN and several
`cytotoxic agents were active against tumorinoculatedi.p., only
`the IFN was active againstthe i.v.-inoculated tumor, suggesting
`that the efficacy of IFN-drug combinations mayreflect actions
`on different populations of tumor cells or on tumorcells at
`different anatomical sites. Of interest
`in this regard is the
`observation that IFN had a selective growth-suppressive effect
`on the hyperdiploid compartmentof a murine colon adenocar-
`cinomacell 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 ez al. (47). Partially
`purified or recombinant IFN-a was found to protect mice from
`the toxic effects of 5-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 vivo 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 marrowcells of the host, thus rendering them less
`sensitive to the cytotoxic actions of the 5-FUra. Presumably
`the protective effect of IFN would allow higher doses of cyto-
`toxic drugs to be used, thus increasing their antitumoractivity
`(48).
`
`Effects on Drug-metabolizing Enzymes
`
`Theearliest evidence for an indirect antitumoreffect of IFN
`was combined in vitro-in vivo studies with mouse L1210 cells.
`IFN directly inhibited the proliferation of L1210 cells in vitro,
`and a variant cell line that was resistant to this effect was
`isolated. Whentested in vivo, IFN hadactivity against both the
`sensitive andresistantcell lines, suggesting that IFN was acting
`in vivo by a host-mediated action (36, 37). Similar conclusions
`were reached using IFN-resistant B-cell lymphomacells (38).
`Another approach to demonstrate indirect host-mediated anti-
`tumoreffects is based on the species specificity of some IFN
`actions. For example, human colon carcinoma cells were im-
`One potential source of indirect interaction of interferons
`planted in nude mice which were then treated with 5-FUrain
`with cytotoxic agents is via the hepatic microsomal enzymes,
`combination wi